Heterocyclic derivatives and use thereof

ABSTRACT

A heterocyclic derivative represented by formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof, which has an inhibitory effect on the activation of STAT3 protein, and is useful for the prevention or treatment of diseases associated with the activation of STAT3 protein.

FIELD OF THE INVENTION

The present invention relates to novel heterocyclic compounds, uses thereof for the prevention or treatment of diseases associated with the activation of STAT proteins, particularly, STAT3 protein and pharmaceutical compositions comprising them.

BACKGROUND OF THE INVENTION

Signal transducer and activator of transcription (STAT) proteins are transcription factors which transduce signals from various extracellular cytokines and growth factors to a nucleus. Seven (7) subtypes of STAT proteins (i.e., STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6) are currently known, and generally they consist of about 750-850 amino acids. In addition, each subtype of STAT proteins contains several conserved domains which play an important role in exhibiting the function of STAT proteins. Specifically, five (5) domains from N-terminus to C-terminus of STAT proteins have been reported including coiled-coiled domain, DNA binding domain, linker domain, SH2 domain and transactivation domain (TAD)). Further, X-ray crystalline structures of STAT1, STAT3, STAT4 and STAT5 have been reported since 1998 (Becker S et al., Nature, 1998, 394; Vinkemeier U et al., Science, 1998, 279; Chen X et al., Cell, 1998, 93; D. Neculai et al., J. Biol. Chem., 2005, 280). In general, receptors to which cytokines and growth factors bind are categorized into Class I and Class II. IL-2, IL-3, IL-5, IL-6, IL-12, G-CSF, GM-CSF, LIF, thrombopoietin, etc., bind to Class I receptors, while INF-α, INF-γ, IL-10, etc., bind to Class II receptors (Schindler C et al., Annu. Rev. Biochem., 1995, 64; Novick D et al., Cell, 1994, 77; Ho AS et al., Proc. Natl. Acad. Sci., 1993, 90). Among them, the cytokine receptors involved in the activation of STAT proteins can be classified depending on their structural forms of extracellular domains into a gp-130 family, an IL-2 family, a growth factor family, an interferon family and a receptor tyrosine kinase family. Interleukin-6 family cytokines are representative multifunctional cytokines which mediate various physiological activities. When interleukin-6 cytokine binds to IL-6 receptor, it attracts gp-130 receptor to form an IL-6-gp-130 receptor complex. At the same time, JAK kinases (JAK1, JAK2, JAK3 and Tyk2) in the cytoplasm are recruited to a cytoplasmic region of gp130 to be phosphorylated and activated. Subsequently, latent cytoplasmic STAT proteins are attracted to a receptor, phosphorylated by JAK kinases and activated. Tyrosine-705 near the SH2 domain located in the C-terminus of STAT proteins is phosphorylated, and the activated tyrosine-705 of each STAT protein monomer binds to the SH2 domain of another monomer in a reciprocal manner, thereby forming a homo- or heterodimer. The dimers are translocalized into a nucleus and bind to a specific DNA binding promoter to promote the transcription. Through its transcription process, various proteins (Myc, Cyclin D1/D2, Bcl-xL, Mcl, survivin, VEGF, HIF-1, immune suppressors, etc.) associated with cell proliferation, survival, angiogenesis and immune evasion are produced (Stark et al., Annu. Rev. Biochem., 1997, 67; Levy et al., Nat. Rev. Mol. Cell Biol., 2002, 3).

In particular, STAT3 protein is known to play a crucial role in the acute inflammatory response and the signal transduction pathway of IL-6 and EGF (Akira et al., Cell, 1994, 76; Zhong et al., Science, 1994, 264). According to the recent clinical report, STAT3 protein is constantly activated in patients with solid cancers occurring in prostate, stomach, breast, lung, pancreas, kidney, uterine, ovary, head and neck, etc., and also in patients with blood cancer such as acute and chronic leukemia, multiple myeloma, etc. Further, it has been reported that the survival rate of a patient group with activated STAT3 is remarkably lower than that of a patient group with inactivated STAT3 (Masuda et al., Cancer Res., 2002, 62; Benekli et al., Blood, 2002, 99; Yuichi et al., Int. J. Oncology, 2007, 30). Meanwhile, STAT3 was identified to be an essential factor for the growth and maintenance of murine embryonic stem cells in a study employing a STAT3 knockout mouse model. Also, a study with a tissue-specific STAT3-deficient mouse model, reveals that STAT3 plays an important role in cell growth, apoptosis, and cell motility in a tissue-specific manner (Akira et al., Oncogene 2000, 19). Moreover, since apoptosis by anti-sensing STAT3 was observed in various cancer cell lines, STAT3 is considered as a promising new anticancer target. STAT3 is also considered as a potential target in the treatment of patients with diabetes, immune-related diseases, hepatitis C, macular degeneration, human papillomavirus infection, non-Hodgkin's lymphoma, tuberculosis, etc. In contrast, although STAT1 has identical intracellular response pathways of cytokines and growth factors to those of STAT3, STAT1 increases inflammation and congenital and acquired immunities to inhibit the proliferation of cancer cells or cause pro-apoptotic responses, unlike STAT3 (Valeria Poli et al., Review, Landes Bioscience, 2009).

In order to develop STAT3 inhibitors, the following methods can be considered: i) inhibition of the phosphorylation of STAT3 protein by IL-6/gp-130/JAK kinase, ii) inhibition of the dimerization of activated STAT3 protein, and iii) inhibition of the binding of STAT3 dimer to nuclear DNA. Small molecular STAT3 inhibitors are currently under development. Specifically, OPB-31121 and OPB-51602 are under clinical studies on patients with solid cancers or blood cancers by Otsuka Pharmaceutical Co., Ltd. Further, S3I-201 (Siddiquee et al., Proc. Natl. Acad. Sci., 2007, 104), S3I-M2001 (Siddiquee et al., Chem. Biol., 2007, 2), LLL-12 (Lin et al., Neoplasia, 2010, 12), Stattic (Schust et al., Chem. Biol. 2006, 13), STA-21 (Song et al., Proc. Natl. Acad. Sci., 2005, 102), SF-1-066 (Zhang et al., Biochem. Pharm., 2010, 79) and STX-0119 (Matsuno et al., ACS Med. Chem. Lett., 2010, 1), etc. have been tested in a cancer cell growth inhibition experiment and in animal model (in vivo Xenograft model). Furthermore, although peptide compounds mimicking the adjacent amino acid sequence of pY-705 (STAT3) which binds to SH2 domain or the amino acid sequence of gp-130 receptor that JAK kinases bind were studied (Coleman et al., J. Med. Chem., 2005, 48), the development of the peptide compounds has not been successful due to the problems such as solubility and membrane permeability.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide novel heterocyclic derivatives for the inhibition of the activation of STAT3 protein.

It is another object of the present invention to provide uses of the heterocyclic derivatives for the prevention or treatment of diseases associated with the activation of STAT3 protein.

In accordance with one aspect of the present invention, there is provided a compound selected from the group consisting of a heterocyclic derivative represented by formula (I), and a pharmaceutically acceptable salt and a stereoisomer thereof:

wherein

A is present or absent, and, if present, A is a saturated or unsaturated C₃₋₁₀ carbocycle or a 5- to 10-membered heterocycle, and if A is absent, X₃ and X₄ are each independently optionally substituted with R₁ or R₂;

B is a benzene or a 5- to 12-membered heterocycle;

C is a benzene, a 5- to 12-membered heterocycle, or C₃₋₆ carbocycle;

Y is —C(═O)— connected to X₂ or X₅;

X₁ is —O—, —S—, —S(═O)—, —S(═O)₂—, or —N(W₁)—;

X₂ is a carbon atom connected to Y, or —N═, —NH—, —C(W₂)═ or —CH(W₂)— not connected to Y;

X₃ and X₄ are each independently a carbon or nitrogen atom;

X₅ is a carbon atom connected to Y, or —CH═ not connected to Y;

-   -   wherein the 5-membered ring comprising X₁ to X₅ is aromatic or         non-aromatic;

W is hydrogen, halogen, C₁₋₆ alkyl, or 5- or 6-membered heterocyclyl-C₁₋₃ alkyl;

W₁ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, or 5- to 8-membered heterocyclyl-C₁₋₄ alkyl;

W₂ is hydrogen, halogen, C₁₋₆ alkyl, or 5- to 8-membered heterocyclyl-C₁₋₄ alkyl;

L is —(CR₉R₁₀)_(m)—, —(CR₉R₁₀)_(m)—O—, —NH—, —N(C₁₋₆ alkyl)-, —S(═O)₂—, —C(═O)—, —C(═CH₂)—, or C₃₋₇ cycloalkylene, wherein m is an integer of 0 to 3, and R₉ and R₁₀ are each independently hydrogen, hydroxy, halogen, or C₁₋₆ alkyl;

R₁ is nitro, amino, C₁₋₆ alkylsulfonyl, haloC₁₋₆ alkoxy, or any one of the following structural formulae i) to iv):

R₂ is hydrogen, halogen, nitro, amino, C₁₋₆alkoxy, haloC₁₋₆alkoxy, C₁₋₆ alkylsulfonyl, or 5- or 6-membered heterocycloalkyl;

R₃ is hydrogen, halogen, cyano, C₁₋₆ alkyl, haloC₁₋₆ alkyl, cyanoC₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, haloC₁₋₆ alkoxy, cyanoC₁₋₆ alkoxy, C₁₋₆ alkylamino, diC₁₋₆ alkylamino, C₁₋₆ alkylthio, C₁₋₆ alkylaminocarbonyl, diC₁₋₆ alkylaminocarbonyl, C₂₋₈ alkynyl, C₆₋₁₀ aryl, haloC₆₋₁₀ aryl, 5- to 10-membered heterocyclyl, or 5- to 10-membered heterocyclylcarbonyl, wherein the heterocyclyl moiety is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C₁₋₆ alkyl, haloC₁₋₆ alkyl, C₁₋₆ alkoxy and C₁₋₆ alkoxycarbonyl;

R₄ is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C₁₋₆ alkylamino, C₁₋₆ alkyl, haloC₁₋₆ alkyl, cyanoC₁₋₆ alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkoxy, cyanoC₁₋₆ alkoxy, C₃₋₈ cycloalkyl-oxy, C₂₋₈ alkynyl, C₁₋₆ alkylamino-C₁₋₆ alkoxy, diC₁₋₆ alkylamino-C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl, carbamoyl, carbamoyl-C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclyl-C₁₋₆ alkyl, 5- to 10-membered heterocyclyl-C₁₋₆ alkoxy, or 5- to 10-membered heterocyclyl-oxy, wherein the heterocyclyl moiety is optionally substituted with one or two substituents selected from the group consisting of hydroxy, oxo, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, diC₁₋₃ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminocarbonyl, diC₁₋₃ alkylaminocarbonyl, C₁₋₆ alkylaminosulfonyl, and non-substituted or C₁₋₆ alkyl-substituted 5- to 10-membered heterocyclyl;

R₅ is hydrogen, C₁₋₆ alkyl, carbamoylC₁₋₆ alkyl, C₁₋₆ alkylaminoC₁₋₆ alkyl, diC₁₋₆ alkylaminoC₁₋₆ alkyl, or 5- to 10-membered heterocyclylC₁₋₆ alkyl, or is fused with R₆ to form C₃₋₄ alkylene;

R₆ is C₁₋₆ alkyl, haloC₁₋₆ alkyl, C₁₋₆ alkoxyC₁₋₆ alkyl, C₁₋₆ alkylcarbonylC₁₋₆ alkyl, C₂₋₇ alkenyl, amino, aminoC₁₋₆ alkyl, C₃₋₇ cycloalkyl, 5- to 10-membered heterocyclyl, or 5- to 10-membered heterocyclyl-C₁₋₆ alkyl, or is fused with R₅ to form C₃₋₄ alkylene, wherein the amino moiety is optionally substituted with one or two substituents selected from hydroxy or C₁₋₆ alkyl, and the heterocyclyl moiety is optionally substituted with one to four substituents selected from the group consisting of oxo, C₁₋₆ alkyl and C₁₋₆ alkylcarbonyl;

R₇ and R₈ are each independently hydrogen or C₁₋₆ alkyl;

p and q are each independently 0 or 1;

r is an integer of 0 to 3, and, when r is 2 or higher, R₃ moieties are the same or different; and

s is an integer of 0 to 3, and, when s is 2 or higher, R₄ moieties are the same or different;

all of said heterocycle or heterocyclyl moieties each independently have a saturated or unsaturated single or multiple ring and contain one to three heteroatoms selected from N, O or S; and all of said aryl moieties each independently have an aromatic single or multiple ring.

In accordance with another aspect of the present invention, there is provided a use of a compound selected from the group consisting of a heterocyclic derivative represented by formula (I) above, and a pharmaceutically acceptable salt and a stereoisomer thereof for the manufacture of a medicament for preventing or treating diseases associated with the activation of STAT3 protein.

In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating diseases associated with the activation of STAT3 protein, comprising a compound selected from the group consisting of a heterocyclic derivative represented by formula (I) above, and a pharmaceutically acceptable salt and a stereoisomer thereof as active ingredients.

In accordance with a still further aspect of the present invention, there is provided a method for preventing or treating diseases associated with the activation of STAT3 protein in a mammal, which comprises administering a compound selected from the group consisting of a heterocyclic derivative represented by formula (I) above, and a pharmaceutically acceptable salt and a stereoisomer thereof to the mammal.

The heterocyclic derivative represented by formula (I) above, or a pharmaceutically acceptable salt or a stereoisomer thereof has an excellent inhibitory effect on the activation of STAT3 protein, and thus it can be used for the prevention or treatment of diseases associated with the activation of STAT3 protein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention will be further described in detail herein below.

In the specification of the present invention, the term “halogen” refers to fluorine, chlorine, bromine or iodine, unless specified otherwise.

The term “alkyl” refers to a linear or branched hydrocarbon residue, unless specified otherwise.

The terms “haloalkyl”, “haloalkoxy”, “halophenyl”, etc., respectively refer to alkyl, alkoxy, and phenyl substituted with at least one halogen.

The term “carbocycle” refers to an aromatic or non-aromatic hydrocarbon ring, which may be saturated or unsaturated, and a monocyclic or polycyclic radical.

The term “carbocyclyl” refers to a radical of “carbocycle”, and is used as a term inclusive of “cycloalkyl” and “aryl”.

The term “cycloalkyl” refers to a saturated hydrocarbon radical, which may be monocyclic or polycyclic.

The term “aryl” refers to an aromatic hydrocarbon ring, which may be monocyclic or polycyclic.

The terms “carbocycle”, “carbocyclyl”, “cycloalkyl” and “aryl” may refer to, for example, a mono- or polycycle having 3 to 20 carbon atoms, and will be indicated as “C₃₋₂₀ carbocycle”, “C₃₋₂₀ carbocyclyl”, “C₃₋₂₀ cycloalkyl”, and “C₃₋₂₀ aryl”, respectively.

The term “heterocycle” refers to an aromatic or non-aromatic ring having at least one heteroatom, which may be saturated or unsaturated, and a monocycle or polycycle.

The term “heterocyclyl”. refers to a radical of “heterocycle”, which is used as a term inclusive of “heterocycloalkyl” and “heteroaryl”.

The term “heterocycloalkyl” refers to a saturated ring radical having at least one heteroatom, which may be monocyclic or polycyclic.

The term “heteroaryl” refers to an aromatic ring radical having at least one heteroatom, which may be monocyclic or polycyclic.

The term “heteroatom” may be selected from N, O and S.

The terms “heterocycle”, “heterocyclyl”, “heterocycloalkyl” and “heteroaryl” may refer to, for example, a mono- or polycycle having 3 to 20 heteroatoms and/or carbon atoms, and will be indicated as “3- to 20-membered heterocycle”, “3- to 20-membered heterocyclyl”, “3- to 20-membered heterocycloalkyl”, and “3- to 20-membered heteroaryl”.

According to an embodiment of the compound of formula (I), the substituents may be defined as follows (definition I):

A is a saturated or unsaturated C₃₋₁₀ carbocycle, or a 5- to 10-membered heterocycle containing one to three heteroatoms selected from N, O or S;

B is benzene or a 5- to 12-membered heterocycle containing one to three N atoms;

C is benzene, or a 5- to 12-membered heterocycle containing one to three heteroatoms selected from N, O or S;

Y is —C(═O)— connected to X₅;

X₁ is —O—, —S—, —S(═O)—, —S(═O)₂—, or —N(W₁)—;

X₂ is —N═, —C(W₂)═ or —CH(W₂)— not connected to Y;

X₃ and X₄ are a carbon atom;

X₅ is a carbon atom connected to Y;

-   -   wherein the 5-membered ring comprising X₁ to X₅ is aromatic or         non-aromatic;

W is hydrogen, halogen, or C₁₋₆ alkyl;

W₁ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, or 5- to 8-membered heterocycloalkyl-C₁₋₄ alkyl containing one or two heteroatoms selected from N or O;

W₂ is hydrogen, C₁₋₆ alkyl, or 5- to 8-membered heterocycloalkyl-C₁₋₄ alkyl containing one or two heteroatoms selected from N or O;

L is —(CR₉R₁₀)_(m)—, —(CR₉R₁₀)_(m)—O—, —NH—, —N(C₁₋₆ alkyl)-, —S(═O)₂—, —C(═O)—, —C(═CH₂)—, or C₃₋₇ cycloalkylene, wherein m is an integer of 0 to 3, and R₉ and R₁₀ are each independently hydrogen, hydroxy, halogen, or C₁₋₆ alkyl;

R₁ is nitro, amino, C₁₋₆ alkylsulfonyl, haloC₁₋₆ alkoxy, or any one of the following structural formulae i) to iv):

R₂ is hydrogen, halogen, C₁₋₆ alkoxy, haloC₁₋₆ alkoxy, or C₁₋₆ alkylsulfonyl;

R₃ is hydrogen, halogen, cyano, C₁₋₆ alkyl, haloC₁₋₆ alkyl, cyanoC₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, haloC₁₋₆ alkoxy, cyanoC₁₋₆ alkoxy, C₁₋₆ alkylamino, diC₁₋₆ alkylamino, C₁₋₆ alkylthio, C₁₋₆ alkylaminocarbonyl, diC₁₋₆ alkylaminocarbonyl, C₂₋₈ alkynyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl containing one or two heteroatoms selected from N or S, 5- to 10-membered heterocycloalkyl containing one or two heteroatoms selected from N or O, or 5- to 10-membered heterocycloalkyl-carbonyl containing one or two heteroatoms selected from N or O;

R₄ is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C₁₋₆ alkylamino, C₁₋₆ alkyl, haloC₁₋₆ alkyl, cyanoC₁₋₆ alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkoxy, cyanoC₁₋₆ alkoxy, C₃₋₈ cycloalkyl-oxy, C₂₋₈alkynyl, C₁₋₆ alkylamino-C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, carbamoyl, carbamoyl-C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, 5- to 10-membered heterocyclyl-C₁₋₆ alkyl containing one or two heteroatoms selected from N or O, 5- to 10-membered heterocyclyl-C₁₋₆ alkoxy containing one or two heteroatoms selected from N or O, or 5- to 10-membered heterocyclyl-oxy containing one or two heteroatoms selected from N or O, wherein the heterocyclyl moiety is optionally substituted with one or two substituents selected from the group consisting of hydroxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminocarbonyl, C₁₋₆ alkylaminosulfonyl, and non-substituted or C₁₋₆ alkyl-substituted 5- to 10-membered heterocyclyl containing one or two heteroatoms selected from N, O or S;

R₅ is hydrogen, C₁₋₆ alkyl, carbamoylC₁₋₆ alkyl, C₁₋₆ alkylamino-C₁₋₆ alkyl, or 5- to 10-membered heterocycloalkyl-C₁₋₆ alkyl containing one to three heteroatoms selected from N, O or S;

R₆ is C₁₋₆ alkyl, haloC₁₋₆ alkyl, C₁₋₆ alkoxyC₁₋₆ alkyl, C₁₋₆ alkylcarbonylC₁₋₆ alkyl, C₂₋₇ alkenyl, amino, aminoC₁₋₆ alkyl, C₃₋₇ cycloalkyl, 5- to 10-membered heterocyclyl containing one to three heteroatoms selected from N, O or S, or 5- to 10-membered heterocyclylC₁₋₆ alkyl containing one to three heteroatoms selected from N, O or S, wherein the amino moiety is optionally substituted with one or two substituents selected from hydroxy or C₁₋₆ alkyl, and the heterocyclyl moiety is optionally substituted with one to four substituents selected from the group consisting of C₁₋₆ alkyl and C₁₋₆ alkylcarbonyl;

R₇ and R₈ are each independently hydrogen or C₁₋₆ alkyl;

-   -   p is 1, and q is 0 or 1;

r is an integer of 0 to 3, and, when r is 2 or higher, R₃ moieties are the same or different; and

s is an integer of 0 to 3, and, when s is 2 or higher, R₄ moieties are the same or different;

all of said heterocycle or heterocyclyl moieties each independently have a saturated or unsaturated single or multiple ring;

all of said heterocycloalkyl moieties each independently have a saturated single or multiple ring; and

all of said aryl or heteroaryl moieties each independently have an aromatic single or multiple ring.

In the definition I, some of the substituents may be defined more specifically as follows (definition Ia):

A is a saturated or unsaturated C₆ carbocycle, or 6-membered heterocycle containing one to three N atoms,

B is benzene, or a 5- to 10-membered heterocycle containing one to three N atoms,

C is benzene, or a 5- to 12-membered heteroaryl containing one to three heteroatoms selected from N, O or S,

L is —(CR₉R₁₀)_(m)—, —O—, —NH—, —N(C₁₋₆ alkyl)-, —S(═O)₂—, —C(═O)—, —C(═CH₂)—, or C₃₋₇ cycloalkylene, wherein m is an integer of 0 to 3, and R₉ and R₁₀ are each independently hydrogen, hydroxy, halogen or C₁₋₆ alkyl; and

R₁ is nitro, amino, or any one of the following structural formulae i) to iv):

wherein R₅ to R₈ are the same as defined in definition I above;

all of said heterocycle moieties each independently have a saturated or unsaturated single or multiple ring; and

said heteroaryl moiety has an aromatic single or multiple ring.

In the definition I, some of the substituents may be defined more specifically as follows (definition Ib):

A is saturated or unsaturated C₃₋₁₀ carbocycle, or 5- to 10-membered heterocycle containing one to three heteroatoms selected from N, O or S;

B is benzene or a 9- to 12-membered heterocycle containing one to three N atoms;

C is benzene, or a 5- to 10-membered heterocycle containing one to three heteroatoms selected from N, O or S;

R₃ is hydrogen, halogen, cyano, C₁₋₆ alkyl, haloC₁₋₆ alkyl, cyanoC₁₋₆ alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkoxy, cyanoC₁₋₆ alkoxy, C₁₋₆ alkylamino, diC₁₋₆ alkylamino, C₁₋₆ alkylaminocarbonyl, diC₁₋₆ alkylaminocarbonyl, C₂₋₈ alkynyl, 5- to 10-membered heterocyclyl containing one to three heteroatoms selected from N, O or S, or 5- to 10-membered heterocycloalkyl-carbonyl containing one or two heteroatoms selected from N or O, wherein the heterocyclyl moiety is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C₁₋₆ alkyl, haloC₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ alkoxycarbonyl; and

-   -   r is 0 or 1;     -   all of said heterocycle moieties and heterocyclyl moieties each         independently have a saturated or unsaturated single or multiple         ring; and     -   said heterocycloalkyl moiety has a saturated single or multiple         ring.

In the definition Ib, some of the substituents may be defined more specifically as the following (i) or (ii):

(i) A is a saturated or unsaturated C₆ carbocycle, or a 6-membered heterocycle containing one to three N atoms.

(ii) B is

and R₃ is the same as defined in definition Ib.

According to another embodiment of the compound of formula (I), the substituents may be defined as follows (definition II):

A is present or absent, and, if present, A is benzene or 6-membered heterocycle containing one to three N atoms, and if A is absent, X₃ and X₄ are each independently optionally substituted with R₁ or R₂;

B is benzene, or a 6- to 10-membered heterocycle containing one to three N atoms;

C is benzene, a 6- to 10-membered heterocycle containing one to three heteroatoms selected from N, O or S, or C₅₋₆ carbocycle;

Y is —C(═O)— connected to X₂ or X₅;

X₁ is —O—, —S—, —S(═O)—, —S(═O)₂—, or —N(W₁)—;

X₂ is a carbon atom connected to Y, or —NH—, —C(W₂)═ or —CH(W₂)— not connected to Y;

X₃ and X₄ are each independently a carbon or nitrogen atom; X₅ is a carbon atom connected to Y, or —CH═ not connected to Y;

wherein the 5-membered ring comprising of X₁ to X₅ is aromatic or non-aromatic;

W is hydrogen, C₁₋₃ alkyl, or 5- or 6-membered heterocycloalkyl-C₁₋₃ alkyl containing one or two heteroatoms selected from N or O;

W₁ is hydrogen, C₁₋₃ alkyl, t-butoxycarbonyl, or 5- or 6-membered heterocycloalkyl-C₁₋₃ alkyl containing one or two heteroatoms selected from N or O;

W₂ is hydrogen, halogen, or C₁₋₃ alkyl;

L is —(CR₉R₁₀)_(m)—, —O—, —S(═O)₂—, C₃₋₆ cycloalkylene, —NH—, —N(C₁₋₃ alkyl)-, —C(═CH₂)—, or —C(═O)—, wherein m is 0 or 1, and R₉ and R₁₀ are each independently hydrogen, halogen, hydroxy or C₁₋₃ alkyl;

R₁ is any one of the following structural formulae i) to iv):

R₂ is hydrogen, halogen, nitro, amino, C₁₋₃ alkoxy, haloC₁₋₃ alkoxy, C₁₋₃ alkylsulfonyl, or 5- or 6-membered heterocycloalkyl containing one or two heteroatoms selected from N or O;

R₃ is hydrogen, halogen, C₁₋₃ alkylcarbonyl, cyano, cyanoC₁₋₃ alkyl, C₁₋₃ alkyl, haloC₁₋₃ alkyl, C₂₋₃ alkynyl, haloC₁₋₃ alkoxy, cyanoC₁₋₃ alkoxy, C₁₋₆ alkoxy, C₁₋₃ alkylamino, diC₁₋₃ alkylamino, C₁₋₃ alkylaminocarbonyl, diC₁₋₃ alkylaminocarbonyl, phenyl, halophenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heterocyclyl-carbonyl, wherein the heterocyclyl moiety contains one to three heteroatoms selected from N, O or S, and is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C₁₋₃ alkyl, haloC₁₋₃ alkyl, C₁₋₃ alkoxy, and t-butoxycarbonyl;

R₄ is hydrogen, oxo, hydroxy, nitro, cyano, halogen, aminosulfonyl, amino, C₁₋₃ alkylamino, diC₁₋₃ alkylamino-C₁₋₃ alkoxy, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, C₁₋₃ alkyl, cyanoC₁₋₃ alkyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, cyanoC₁₋₃ alkoxy, haloC₁₋₃ alkoxy, carbamoyl-C₁₋₃ alkoxy, C₃₋₆ cycloalkyl-oxy, 4- to 10-membered heterocyclyl, 4- to 10-membered heterocyclyl-oxy, or 4- to 10-membered heterocyclyl-C₁₋₃ alkyl, wherein the heterocyclyl moiety contains one to three heteroatoms selected from N, O or S, and is optionally substituted with one or two substituents selected from the group consisting of hydroxy, oxo, C₁₋₃ alkyl, t-butylcarbonyl, t-butoxycarbonyl, C₁₋₃ alkylsulfonyl, diC₁₋₃ alkylsulfonyl, diC₁₋₃ alkylaminocarbonyl, 4- to 6-membered heterocyclyl and C₁₋₆ alkyl-substituted 4- to 6-membered heterocyclyl;

R₅ is hydrogen, C₁₋₃ alkyl, carbamoylC₁₋₃ alkyl, diC₁₋₃ alkylamino-C₁₋₃ alkyl, or morpholino-C₁₋₃ alkyl, or is fused with R₆ to form C₃₋₄ alkylene;

R₆ is C₁₋₃ alkyl, haloC₁₋₃ alkyl, C₁₋₃ alkoxyC₁₋₃ alkyl, C₂₋₃ alkenyl, amino, aminoC₁₋₃ alkyl, C₃₋₆ cycloalkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heterocyclyl-C₁₋₃ alkyl, or is fused with R₅ to form C₃₋₄ alkylene, wherein the heterocyclyl moiety contains one to three heteroatoms selected from N, O or S, and is optionally substituted with one to four substituents selected from the group consisting of hydrogen, oxo, C₁₋₃ alkyl and acetyl, and the amino moiety is unsubstituted or substituted with one or two substituents selected from hydroxy or C₁₋₃ alkyl;

R₇ is hydrogen or C₁₋₃ alkyl;

R₈ is hydrogen or C₁₋₆ alkyl;

p and q are each independently 0 or 1;

r is 0 or 1; and

s is an integer of 0 to 3, and, when s is 2 or higher, R₄ moieties are the same or different;

all of said heterocycle and heterocyclyl moieties each independently have a saturated or unsaturated single or double ring.

In the definition II, some of the substituents may be defined more specifically as the following (i), (ii), (iii) or (iv):

(i) B is

and R₃ is the same as defined in definition II.

-   -   (ii) m is 1; and R₉ and R₁₀ are each independently halogen,         hydroxy, or C₁₋₃ alkyl.

(iii) m is 0; and R₃ is hydrogen, phenyl, halophenyl, saturated or unsaturated 5- or 6-membered heterocyclyl or 5- to 6-membered heterocyclyl-carbonyl wherein the heterocyclyl moiety contains one to three heteroatoms selected from N, O or S, and is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C₁₋₃ alkyl, haloC₁₋₃ alkyl, C₁₋₃ alkoxy, and t-butoxycarbonyl.

(iv) X₁ is —S— or —NH—; X₂ is —CH═ not connected to Y; X₃ and X₄ are a carbon atom; and R₁ is the structural formula i).

Preferable examples of the compound according to the present invention are listed below, and a pharmaceutically acceptable salt and a stereoisomer thereof are also included in the scope of the present invention:

-   1)     N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   2)     6-(methylsulfonamido)-N-(3-(2-phenylpropan-2-yl)phenyl)-1H-indole-2-carboxamide; -   3)     N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   4)     N-(3-methoxy-5-(2-(3-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   5)     N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxamide; -   6)     N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonyl)-1H-indole-2-carboxamide; -   7)     N-(3-(2-(2-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   8)     6-(methylsulfonamido)-N-(3-(2-(3-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-1H-indole-2-carboxamide; -   9)     N-(3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   10)     N-(3-(1-(3-methoxy-5-(trifluoromethoxy)phenyl)ethyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   11)     N-(3-(2-(2,4-difluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   12)     N-(3-(2-(3-methoxyphenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   13)     N-(3-methoxy-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   14)     N-(3-bromo-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   15)     N-(3-bromo-5-(2-(2,4-difluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   16)     N-(3-bromo-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   17)     N-(3-(difluoromethoxy)-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   18)     N-(3-(2-(3-(2-amino-2-oxoethoxy)phenyl)propan-2-yl)-5-bromophenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   19)     N-(3-bromo-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   20)     N-(3-bromo-5-(2-(3-(difluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   21)     N-(3-chloro-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   22)     N-(3-bromo-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   23)     N-(3-bromo-5-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   24)     N-(3-chloro-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   25)     N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(trifluoromethoxy)-1H-indole-2-carboxamide; -   26)     N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   27)     N-(3-(2-(2,4-difluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   28)     N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzofuran-2-carboxamide; -   29)     N-(3-(2-(2,4-difluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzofuran-2-carboxamide; -   30)     N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   31)     N-(3-(2-(2-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   32)     N-(3-bromo-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   33)     N-(3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   34)     N-(3-methoxy-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   35)     N-(3-bromo-5-(2-(2,4-difluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   36)     N-(3-bromo-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   37)     5-(methylsulfonamido)-N-(3-(2-(3-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide; -   38)     N-(3-(2-(3-methoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   39)     N-(3-(difluoromethoxy)-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   40)     N-(3-chloro-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   41)     N-(3-(difluoromethoxy)-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   42)     N-(3-chloro-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   43)     N-(3-(2-(3-(2-amino-2-oxoethoxy)phenyl)propan-2-yl)-5-bromophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   44)     N-(3-(2-(5-(2-amino-2-oxoethoxy)-2-fluorophenyl)propan-2-yl)-5-bromophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   45)     N-(3-(2-(3-((1-amino-2-methyl-1-oxopropan-2-yl)oxy)phenyl)propan-2-yl)-5-bromophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   46)     N-(3-bromo-5-(2-(3-(difluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   47)     N-(3-bromo-5-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   48)     N-(3-bromo-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   49)     N-(3-bromo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   50)     N-(3-bromo-5-(2-(3-(morpholinomethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   51)     N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   52)     N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-3-methyl-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   53)     N-(3-bromo-5-(3-(4-fluorophenyl)pentan-3-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   54)     N-(3-methoxy-5-(3-(3-methoxy-5-(trifluoromethoxy)phenyl)pentan-3-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   55)     N-(3-methoxy-5-(3-(3-methoxy-5-(trifluoromethoxy)phenyl)pentan-3-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   56)     N-(3-bromo-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-b]pyridine-2-carboxamide; -   57)     N-(3-chloro-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-b]pyridine-2-carboxamide; -   58)     N-(3-chloro-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   59)     N-(3-chloro-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   60)     N-(3-bromo-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[3,2-b]pyridine-2-carboxamide; -   61)     N-(3-bromo-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-c]pyridine-2-carboxamide; -   62)     N-(3-chloro-5-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   63)     N-(3-fluoro-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   64)     N-(3-chloro-5-(2-phenylpropan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   65)     N-(3-chloro-5-(2-(3-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   66)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)-4-morpholinobenzo[b]thiophene-2-carboxamide; -   67)     N-(3-chloro-5-(2-(3-fluoro-5-methoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   68)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   69)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-b]pyridine-2-carboxamide; -   70)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[3,2-b]pyridine-2-carboxamide; -   71)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-c]pyridine-2-carboxamide; -   72)     N-(3-chloro-5-(2-(3-isobutoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   73)     N-(3-chloro-5-(2-(3-propoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   74)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxamide; -   75)     N-(3-(2-(3-(but-2-yn-1-yloxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   76)     N-(3-chloro-5-(2-(3-(oxetan-3-yloxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   77)     N-(3-chloro-5-(2-(3-(cyanomethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   78)     N-(3-(2-(3-(allyloxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   79)     N-(3-chloro-5-(2-(3-cyclopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   80)     N-(3-chloro-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   81)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[d]thiazole-2-carboxamide; -   82)     N-(3-fluoro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   83)     N-(3-chloro-5-(2-(3-(2,2-difluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   84)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   85)     N-(3-fluoro-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   86)     N-(3-fluoro-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-c]pyridine-2-carboxamide; -   87)     N-(3-bromo-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   88)     N-(3-chloro-5-(2-(3-(2,2,2-trifluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   89)     N-(3-bromo-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-c]pyridine-2-carboxamide; -   90)     N-(3-chloro-5-(2-(3-(2-morpholinoethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   91)     N-(3-(2-(3-bromo-5-isopropoxyphenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   92)     N-(3-chloro-5-(2-(3-chloro-5-isopropoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   93)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-4-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   94) N-(3-chloro-5-(2-(3-(2-(dimethyl     amino)ethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   95) tert-butyl     4-(3-(2-(3-chloro-5-(5-(methylsulfonamido)benzo[b]thiophene-2-carboxamido)phenyl)propan-2-yl)-5-(trifluoromethoxy)phenoxy)piperidine-1-carboxylate; -   96)     N-(3-chloro-5-(2-(3-(piperidin-4-yloxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   97)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide; -   98)     N-(3-bromo-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide; -   99)     N-(3-bromo-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide     2,2,2-trifluoroacetate; -   100)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; -   101)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide; -   102)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-4-(methylsulfonamido)thiophene-2-carboxamide; -   103)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(morpholine-4-sulfonamido)benzo[b]thiophene-2-carboxamide; -   104)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide; -   105)     6-chloro-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   106)     N-(3-chloro-5-(2-(3-methoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   107)     N-(3-ethynyl-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   108)     N-(3-ethynyl-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   109)     N-(3-(2-(2,4-difluorophenyl)propan-2-yl)-5-ethynylphenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   110)     3-chloro-N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   111)     3-chloro-N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   112)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-7-methoxy-5-(methylsulfonamido)benzofuran-2-carboxamide; -   113)     N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-7-methoxy-5-(methylsulfonamido)benzofuran-2-carboxamide; -   114)     N-(3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   115)     N-(3-bromo-5-(2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   116) tert-butyl     4-(3-(2-(3-bromo-5-(5-(methylsulfonamido)benzo[b]thiophene-2-carboxamido)phenyl)propan-2-yl)benzyl)piperazine-1-carboxylate; -   117) tert-butyl     4-(3-(2-(3-bromo-5-(6-(methylsulfonamido)-1H-indole-2-carboxamido)phenyl)propan-2-yl)benzyl)piperazine-1-carboxylate; -   118)     N-(3-bromo-5-(2-(3-(piperazin-1-ylmethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   119)     N-(3-bromo-5-(2-(3-(piperazin-1-ylmethyl)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   120)     N-(3-(2-(3-((1H-imidazol-1-yl)methyl)phenyl)propan-2-yl)-5-bromophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   121)     N-(3-chloro-5-(2-(3-((2-hydroxyazetidin-1-yl)methyl)-5-isopropoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   122)     N-(3-bromo-5-(2-(3-isopropoxy-5-(morpholinomethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   123) tert-butyl     4-(3-(2-(3-bromo-5-(5-(methylsulfonamido)benzo[b]thiophene-2-carboxamido)phenyl)propan-2-yl)-5-isopropoxybenzyl)piperazine-1-carboxylate; -   124)     N-(3-bromo-5-(2-(3-isopropoxy-5-(piperazin-1-ylmethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   125)     N-(3-chloro-5-(2-(3-isopropoxy-5-(pyrrolidin-1-ylmethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   126)     N-(3-chloro-5-(2-(3-isopropoxy-5-(morpholinomethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   127)     N-(3-chloro-5-(2-(3-isopropoxy-5-((4-pivaloylpiperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   128)     N-(3-chloro-5-(2-(3-isopropoxy-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   129)     N-(3-chloro-5-(2-(3-isopropoxy-5-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)piperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   130)     N-(3-chloro-5-(2-(3-isopropoxy-5-((4-(oxetan-3-yl)piperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   131)     N-(3-chloro-5-(2-(3-((4-(N,N-dimethylsulfamoyl)piperazin-1-yl)methyl)-5-isopropoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   132)     N-(3-chloro-5-(2-(3-((1,1-dioxidothiomorpholino)methyl)-5-isopropoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   133)     4-(3-(2-(3-chloro-5-(5-(methylsulfonamido)benzo[b]thiophene-2-carboxamido)phenyl)propan-2-yl)-5-isopropoxybenzyl)-N,N-dimethylpiperazine-1-carboxamide; -   134)     N-(3-(2-(3-((2-oxa-7-azaspiro[3,5]nonan-7-yl)methyl)-5-isopropoxyphenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   135)     N-(3-chloro-5-(2-(3-isopropoxy-5-((4-(5-isopropyl-1,3,4-oxadiazol-2-yl)piperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   136)     N-(3-fluoro-5-(2-(3-isopropoxy-5-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)piperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   137)     N-(3-fluoro-5-(2-(3-isopropoxy-5-(morpholinomethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   138)     N-(3-chloro-5-(2-(3-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   139)     N-(3-bromo-5-(2-(3-((4-(N,N-dimethylsulfamoyl)piperazin-1-yl)methyl)-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   140)     N-(3-fluoro-5-(2-(3-(morpholinomethyl)-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   141)     N-(3-bromo-5-(2-(3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide, -   142)     N-(3-chloro-5-(2-(3-isopropoxy-5-(1-methyl-1H-pyrazol-5-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   143)     N-(3-chloro-5-(2-(3-isopropoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   144)     N-(3-chloro-5-(2-(3-(3-hydroxy-4-methylpiperazin-1-yl)-5-isopropoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   145)     N-(3-chloro-5-(2-(3-isopropoxy-5-morpholinophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   146)     N-(3-chloro-5-(2-(3-isopropoxy-5-(pyrrolidin-1-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   147)     N-(3-chloro-5-(2-(3-isopropoxy-5-(4-methylpiperazin-1-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   148)     N-(6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   149)     N-(2-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   150)     N-(4-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   151)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-2-(methylsulfonamido)thieno[2,3-b]pyrazine-6-carboxamide; -   152)     N-(3-(2-(4-bromophenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   153)     N-(3-chloro-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   154)     N-(3-chloro-5-(2-(2,4-dimethoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   155)     N-(3-chloro-5-(2-(4-methoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   156)     N-(3-chloro-5-(2-(2,5-dimethoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   157)     N-(3-chloro-5-(2-(4-(methylthio)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   158)     N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   159)     N-(3-chloro-5-(2-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   160)     N-(3-chloro-5-(2-(4-(methylsulfinyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   161)     N-(3-chloro-5-(2-(4-(methylsulfonyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   162)     N-(3-chloro-5-(2-(3,4-difluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   163)     N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; -   164)     N-(3-chloro-5-(2-(piperidin-1-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   165)     6-chloro-N-(3-chloro-5-(2-(piperidin-1-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   166)     N-(3-(2-(1H-pyrrol-2-yl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   167)     N-(3-(2-(1H-pyrrol-3-yl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   168)     N-(3-chloro-5-(2-(1-methyl-1H-pyrrol-3-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   169)     N-(3-chloro-5-(2-(1-methyl-1H-pyrrol-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   170)     N-(3-chloro-5-(2-(thiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   171)     N-(3-chloro-5-(2-(thiophen-3-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   172)     6-chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   173)     6-bromo-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   174)     N-(3-chloro-5-(2-(5-chlorothiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   175)     6-chloro-N-(3-chloro-5-(2-(5-chlorothiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   176)     N-(3-chloro-5-(2-(2-methoxythiophen-3-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-arboxamide; -   177)     N-(3-chloro-5-(2-(5-methoxythiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   178)     N-(3-chloro-5-(2-(5-methylthiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   179)     6-chloro-N-(3-chloro-5-(2-(5-methylthiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   180)     6-chloro-N-(3-chloro-5-(2-(5-isopropylthiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   181)     6-chloro-N-(3-chloro-5-(2-(4-methylthiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   182)     6-chloro-N-(3-chloro-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   183)     6-chloro-N-(3-chloro-5-(2-(4-methoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   184)     5-chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   185)     6-chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-((2-methoxyethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; -   186)     6-chloro-N-(3-chloro-5-(2-(5-cyanothiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   187)     N-(3-chloro-5-(2-(1-ethyl-1H-pyrrol-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   188)     6-chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-((2-hydroxyethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; -   189)     N-(3-chloro-5-(2-(pyrimidin-2-yloxy)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   190)     N-(3-chloro-5-(2-(6-oxopyridazin-1(6H)-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   191)     N-(3-chloro-5-(2-(pyridin-4-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   192)     2-((3-bromo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl     dihydrogen phosphate; -   193)     2-((3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl     dihydrogen phosphate; -   194) tert-butyl     (2-((3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl)carbamate; -   195)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((2-methoxyethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; -   196)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(((tetrahydrofuran-3-yl)methyl)sulfonamido)benzo[b]thiophene-2-carboxamide; -   197)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(((tetrahydrofuran-2-yl)methyl)sulfonamido)benzo[b]thiophene-2-carboxamide; -   198)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonamido)benzo[b]thiophene-2-carboxamide; -   199)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((3,5-dimethylisoxazole)-4-sulfonamido)benzo[b]thiophene-2-carboxamide; -   200)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((1-methyl-1H-pyrazole)-3-sulfonamido)benzo[b]thiophene-2-carboxamide; -   201)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((1-methyl-1H-pyrazole)-4-sulfonamido)benzo[b]thiophene-2-carboxamide; -   202)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(ethylsulfonamido)benzo[b]thiophene-2-carboxamide; -   203)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((1-methylethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; -   204)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxamide; -   205)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((1,1-dioxidotetrahydro-2H-thiopyran)-4-sulfonamido)benzo[b]thiophene-2-carboxamide; -   206)     5-((1-acetylpiperidine)-4-sulfonamido)-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide; -   207)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(vinylsulfonamido)benzo[b]thiophene-2-carboxamide; -   208)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((2-(dimethylamino)ethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; -   209)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((2-morpholinoethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; -   210)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((2-(hydroxy(methyl)amino)ethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; -   211)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(1,1-dioxido-1,2-thiazinan-2-yl)benzo[b]thiophene-2-carboxamide; -   212)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(1,1-dioxidoisothiazolidin-2-yl)benzo[b]thiophene-2-carboxamide; -   213)     N-(3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   214)     3-iodo-N-(3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   215)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; -   216)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-N-methyl-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; -   217)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-5-(N-(2-morpholinoethyl)methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   218)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-N-(2-morpholinoethyl)-5-(N-(2-morpholinoethyl)methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   219)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(N-(2-(dimethylamino)ethyl)methylsulfonamido)-6-fluorobenzo[b]thiophene-2-carboxamide; -   220)     N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; -   221)     N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide, -   222)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide     1,1-dioxide; -   223)     N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide     1-oxide; -   224)     N-(3-(2-(3-cyanophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   225)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide; -   226)     6-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   227)     5-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   228)     3-methyl-5-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   229)     N-(4′-fluoro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-nitroindoline-2-carboxamide; -   230)     6-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)indoline-2-carboxamide; -   231)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-nitroindoline-2-carboxamide; -   232)     6-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)benzo[d]thiazole-2-carboxamide; -   233)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-nitro-1H-benzo[d]imidazole-2-carboxamide; -   234)     5-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazole-2-carboxamide, -   235)     N-(4′-fluoro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-5-nitro-1H-benzo[d]imidazole-2-carboxamide; -   236)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   237)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   238)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzofuran-2-carboxamide; -   239)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxamide; -   240)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonyl)-1H-indole-2-carboxamide; -   241)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   242)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   243)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3-methyl-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   244)     N-(4′-fluoro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide; -   245)     N-(5-acetyl-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   246)     N-(4-(2,4-difluorophenyl)-1H-indazol-6-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   247)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-nitro-1H-indole-2-carboxamide; -   248)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-(methylsulfonamido)-1H-indole-2-carboxamide, -   249)     1-methyl-6-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   250)     1-methyl-5-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   251) 3-methyl-1-(2-morpholino     ethyl)-5-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   252)     1-(2-morpholinoethyl)-6-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   253)     1-methyl-6-(methylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   254)     2-((2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indol-6-yl)oxy)-2-methylpropanoic     acid; -   255) ethyl     2-((2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indol-6-yl)oxy)acetate; -   256)     2-((2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indol-6-yl)oxy)acetic     acid; -   257)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxamide; -   258)     5-amino-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   259)     5-(methylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   260)     6-(methylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   261)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)indoline-2-carboxamide; -   262)     N-(4′-fluoro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)indoline-2-carboxamide; -   263) tert-butyl     6-nitro-2-((2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indole-1-carboxylate; -   264) 6-(2,2,2-trifluoroethyl     sulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   265)     6-(sulfamoylamino)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   266)     6-(methylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-3-carboxamide; -   267)     6-((N,N-dimethylsulfamoyl)amino)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   268)     N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(trifluoromethylsulfonamido)-1H-indole-2-carboxamide; -   269)     64N-methylsulfamoyl)amino)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   270)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   271)     6-amino-N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   272)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)-1H-indole-2-carboxamide; -   273) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(2,2,2-trifluoro     ethylsulfonamido)-1H-indole-2-carboxamide; -   274)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(sulfamoylamino)-1H-indole-2-carboxamide; -   275)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-3-carboxamide; -   276)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-((N,N-dimethylsulfamoyl)amino)-1H-indole-2-carboxamide; -   277)     N-(4′-fluoro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   278)     6-(cyclopropanesulfonamido)-N-(4-(2,4-difluorophenyl)pyridin-2-yl)-1H-indole-2-carboxamide; -   279)     N-(4-(2,4-difluorophenyl)pyridin-2-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   280)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-N-methyl-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   281)     N-(5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   282)     N-(5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide; -   283)     6-(methylsulfonamido)-N-(4′-sulfamoyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   284)     N-(4′-cyano-T-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   285)     6-(methylsulfonamido)-N-(4′-nitro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   286) methyl     3′-(6-nitro-1H-indole-2-carboxamido)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylate; -   287) methyl     3′-(6-(methylsulfonamido)-1H-indole-2-carboxamido)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylate; -   288) methyl     4-methoxy-3′-(6-nitro-1H-indole-2-carboxamido)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylate; -   289) methyl     4-methoxy-3′-(6-(methylsulfonamido)-1H-indole-2-carboxamido)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylate; -   290)     6-(methylsulfonamido)-N-(3-(3-(trifluoromethyl)pyridin-2-yl)phenyl)-1H-indole-2-carboxamide; -   291)     6-(methylsulfonamido)-N-(3-(4-(trifluoromethyl)pyridin-3-yl)phenyl)-1H-indole-2-carboxamide; -   292)     6-nitro-N-(3-(2-(trifluoromethyl)pyridin-3-yl)phenyl)-1H-indole-2-carboxamide; -   293)     6-(methylsulfonamido)-N-(3-(2-(trifluoromethyl)pyridin-3-yl)phenyl)-1H-indole-2-carboxamide; -   294)     N-(3-(6-chloro-4-(trifluoromethyl)pyridin-3-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   295)     N-(2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide; -   296) tert-butyl     2-((2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)carbamoyl)-6-(methylsulfonamido)-1H-indole-1-carboxylate; -   297)     N-(4-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)-6-nitro-1H-indole-2-carboxamide; -   298) methyl     6-chloro-3′-(6-nitro-1H-indole-2-carboxamido)-[1,1′-biphenyl]-3-carboxylate; -   299) methyl     6-chloro-3′-(6-(methylsulfonamido)-1H-indole-2-carboxamido)-[1,1′-biphenyl]-3-carboxylate; -   300) methyl     4-chloro-3-(2-(6-(methylsulfonamido)-1H-indole-2-carboxamido)pyridin-4-yl)benzoate; -   301)     N-(5-cyano-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   302)     N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   303)     N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   304)     N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonyl)-1H-indole-2-carboxamide; -   305)     N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   306)     N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzofuran-2-carboxamide; -   307)     N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxamide; -   308)     N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxamide; -   309)     N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   310)     N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   311)     N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3-methyl-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   312)     6-(methylsulfonamido)-N-(2′,4′,5-trifluoro-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   313)     N-(2′,4′-difluoro-5-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   314)     N-(2′,4′-difluoro-5-methoxy-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   315)     N-(5-cyano-4′-fluoro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   316)     N-(2′,4′-difluoro-5-methoxy-[1,1′-biphenyl]-3-yl)-3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   317)     N-(2′,4′-difluoro-5-methoxy-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   318)     N-(2′,4′-difluoro-5-(methylcarbamoyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   319)     N-(5-(dimethylcarbamoyl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   320)     N-(2′,4′-difluoro-5-(piperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   321)     N-(2′,4′-difluoro-5-(morpholine-4-carbonyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   322)     N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   323)     N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   324)     N-(5-chloro-3′-methoxy-5′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   325)     N-(5-chloro-3′-methoxy-5′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)-6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   326)     N-(5-chloro-3′-methoxy-5′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)-6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; -   327)     N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxamide; -   328)     N-(5-chloro-3′-methoxy-5′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)-5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxamide; -   329)     N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; -   330)     N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-fluoro-5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxamide; -   331)     N-(4-chloro-6-(2,4-difluorophenyl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   332)     N-(3-chloro-5-(thiophen-3-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   333)     6-chloro-N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   334)     N-(3-chloro-5-(1-methyl-1H-pyrrol-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   335)     N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3-hydroxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   336)     N-(3-chloro-5-(thiophen-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   337)     N-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   338)     N-(3-chloro-5-(pyrazin-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   339)     N-(3-chloro-5-(6-chloropyrazin-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   340)     N-(3-chloro-5-(1-methyl-1H-imidazol-5-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   341)     N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide; -   342)     N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide; -   343)     1-methyl-6-(N-methylmethylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   344)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide; -   345)     N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide; -   346)     6-(N-methylmethylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; -   347)     N-(2′,4′-difluoro-5-methoxy-[1,1′-biphenyl]-3-yl)-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide; -   348)     N-(2′,4′-difluoro-5-methoxy-[1,1′-biphenyl]-3-yl)-1-methyl-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide; -   349)     N-(2′,4′-difluoro-5-(6-fluoropyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   350) tert-butyl     2-(2′,4′-difluoro-5-(6-(methylsulfonamido)-1H-indole-2-carboxamido)-[1,1′-biphenyl]-3-yl)-1H-pyrrole-1-carboxylate; -   351)     N-(2′,4′-difluoro-5-(1H-pyrazol-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   352)     N-(2′,4′-difluoro-5-(1H-pyrrol-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   353)     N-(2′,4′-difluoro-5-(1-methyl-1H-pyrrol-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   354)     N-(2′,4′-difluoro-5-(thiophen-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   355)     N-(2′,4′-difluoro-5-(thiophen-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   356)     N-(2′,4′-difluoro-5-(pyridin-4-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   357)     N-(2′,4′-difluoro-5-(pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   358)     N-(2′,4′-difluoro-5-(6-(trifluoromethyl)pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   359)     N-(5-(6-cyanopyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   360)     N-(2′,4′-difluoro-5-(pyrimidin-5-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   361)     N-(5-(2-aminopyrimidin-5-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   362)     6-(methylsulfonamido)-N-(2,2″,4,4″-tetrafluoro-[1,1′:3′,1″-terphenyl]-5′-yl)-1H-indole-2-carboxamide; -   363)     N-(5-(cyanomethyl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   364)     N-(2′,4′-difluoro-5-(6-hydroxypyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   365)     N-(5-ethynyl-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   366)     N-(5-(2,2-difluoroethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   367)     N-(2′,4′-difluoro-5-isobutoxy-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   368)     N-(5-(cyanomethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   369)     N-(5-(difluoromethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide, -   370)     N-(5-(difluoromethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   371)     N-(2′,4′-difluoro-5-(piperidin-1-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   372)     N-(5-(dimethylamino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   373)     N-(2′,4′-difluoro-5-(methylamino)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   374)     N-(2′,4′-difluoro-5-morpholino-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   375)     N-(5-(dimethylamino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   376)     N-(5-(dimethylamino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzofuran-2-carboxamide; -   377)     N-(5′-carbamoyl-4′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   378)     N-(5′-carbamoyl-4′-hydroxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   379)     N-(5′-carbamoyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   380)     N-(5′-carbamoyl-2′-chloro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   381)     N-(4-(5-carbamoyl-2-chlorophenyl)pyridin-2-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   382)     N-(2′,4′-difluoro-5-(6-methoxypyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   383)     N-(2′,4′-difluoro-5-(6-methoxypyridin-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   384)     N-(2′,4′-difluoro-5-(6-hydroxypyridin-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   385)     N-(4′-amino-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   386)     N-(4′-(methylamino)-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   387)     N-(3-(difluoro(phenyl)methyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   388)     N-(3-(difluoro(pyridin-4-yl)methyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   389)     N-(3-(difluoro(pyridin-2-yl)methyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   390)     N-(3-((3-cyanophenyl)difluoromethyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   391)     N-(3-((3-cyanophenyl)difluoromethyl)-5-(2,2-difluoroethoxy)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   392)     N-(3-((3-cyanophenyl)difluoromethyl)-5-isobutoxyphenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   393)     N-(3-(cyanomethoxy)-5-((3-cyanophenyl)difluoromethyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   394)     N-(3-((4-methoxyphenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   395) 6-(methylsulfonamido)-N-(3-(phenyl     sulfonyl)phenyl)-1H-indole-2-carboxamide; -   396)     6-(methylsulfonamido)-N-(3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-1H-indole-2-carboxamide; -   397)     N-(3-methoxy-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   398)     6-(methylsulfonamido)-N-(3-((3-(trifluoromethoxy)phenyl)sulfonyl)-5-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide; -   399)     N-(3-cyano-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   400)     N-(3-isobutoxy-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   401)     N-(3-(2,2-difluoroethoxy)-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   402)     N-(3-((3-cyanophenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   403)     6-(methylsulfonamido)-N-(3-(pyridin-2-ylsulfonyl)phenyl)-1H-indole-2-carboxamide; -   404) 6-(methylsulfonamido)-N-(3-(pyridin-3-yl     sulfonyl)phenyl)-1H-indole-2-carboxamide; -   405)     N-(3-((3-chlorophenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   406)     N-(3-((6-cyanopyridin-2-yl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   407)     N-(3-((5-methoxypyridin-3-yl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   408)     N-(3-((6-methoxypyridin-2-yl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   409)     N-(3-(benzo[b]thiophen-5-ylsulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   410)     N-(3-((2-methylbenzo[d]thiazol-6-yl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   411)     N-(3-((3-cyano-5-methoxyphenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   412)     N-(3-((3-(cyanomethyl)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   413)     6-(methylsulfonamido)-N-(3-((4-oxo-4H-chromen-7-yl)sulfonyl)phenyl)-1H-indole-2-carboxamide; -   414)     N-(3-((3-bromophenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   415) N-(3-((3-aminophenyl)     sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   416)     N-(3-ethynylphenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   417)     N-(3-((3-cyano-5-hydroxyphenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide, -   418)     N-(3-bromo-5-((7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   419)     N-(3-bromo-5-((5,7-difluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   420)     N-(3-bromo-5-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   421)     5-(methylsulfonamido)-N-(3-(1-phenylcyclopropyl)phenyl)benzo[b]thiophene-2-carboxamide; -   422)     6-(methylsulfonamido)-N-(3-(1-phenylcyclopropyl)phenyl)-1H-indole-2-carboxamide; -   423)     5-(methylsulfonamido)-N-(3-(1-phenylvinyl)phenyl)benzo[b]thiophene-2-carboxamide; -   424)     N-(3-(1-(4-fluorophenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   425)     N-(3-(1-(4-fluorophenyl)cyclopropyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   426)     N-(3-bromo-5-(1-(2,4-difluorophenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   427)     N-(3-methoxy-5-(1-(3-methoxy-5-(trifluoromethoxy)phenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   428) N-(3-(difluoromethoxy)-5-(1-(4-fluorophenyl)     cyclopropyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   429)     N-(3-(difluoromethoxy)-5-(1-(4-fluorophenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   430)     N-(3-chloro-5-(1-(3-isopropoxy-5-(trifluoromethoxy)phenyl)cyclopropyl)phenyl)-6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; -   431)     N-(3-chloro-5-(1-(3-isopropoxy-5-(trifluoromethoxy)phenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   432)     N-(3-chloro-5-(1-(4-chlorophenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   433)     6-chloro-N-(3-chloro-5-(1-(4-chlorophenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   434)     N-(3-benzoylphenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   435)     N-(3-(1-hydroxy-1-phenylethyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; -   436)     6-(N-(2-amino-2-oxoethyl)methylsulfonamido)-N-(3-(2-(3-hydroxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-1H-indole-2-carboxamide; -   437)     N-(3-(2-(3-(2-amino-2-oxoethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(N-(2-amino-2-oxoethyl)methylsulfonamido)-1H-indole-2-carboxamide; -   438)     N-(3-chloro-5-((2,4-difluorophenyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   439)     N-(3-chloro-5-((2,4-difluorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   440)     N-(3-chloro-5-((4-chlorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   441)     6-chloro-N-(3-chloro-5-((4-chlorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   442)     6-chloro-N-(3-chloro-5-((2,4-difluorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   443)     N-(3-chloro-5-((3-isopropoxy-5-(trifluoromethoxy)phenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   444)     N-(3-chloro-5-(2,4-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   445)     N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   446)     N-(3-chloro-5-(4-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   447)     N-(3-chloro-5-(4-methoxyphenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   448)     N-(3-chloro-5-(2,5-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   449)     6-chloro-N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide, -   450)     N-(3-chloro-5-(3-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   451)     N-(3-chloro-5-(4-cyanophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   452)     N-(3-chloro-5-(3-isopropoxy-5-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   453)     6-bromo-N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   454)     N-(3-chloro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   455)     N-(3-chloro-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   456)     N-(3-chloro-5-(3-chlorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   457)     N-(3-chloro-5-(3-methoxyphenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   458)     N-(3-chloro-5-(3-chloro-5-cyanophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   459)     N-(3-chloro-5-(3-cyanophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   460)     N-(3-chloro-5-(3,4-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   461)     N-(3-chloro-5-(3-chloro-4-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   462)     N-(3-chloro-5-(2,4-dichlorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   463)     N-(3-chloro-5-(3,5-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   464)     N-(3-chloro-5-(3,5-dichlorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   465)     N-(3-chloro-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   466)     N-(3-chloro-5-(4-chloro-3-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   467)     N-(3-chloro-5-(3-chloro-5-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   468)     N-(3-chloro-5-(4-chloro-3-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   469)     N-(3-chloro-5-(3-chloro-5-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   470)     N-(3-chloro-5-(4-fluoro-3-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   471)     6-chloro-N-(3-chloro-5-(thiazol-2-yloxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   472)     6-chloro-N-(3-chloro-5-(thiazol-5-yloxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   473)     6-chloro-N-(3-chloro-5-((5-chlorothiophen-2-yl)oxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   474)     6-chloro-N-(3-chloro-5-(3-chloro-5-methoxyphenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   475)     6-chloro-N-(3-chloro-5-(3-chloro-5-hydroxyphenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   476)     6-chloro-N-(3-chloro-5-(3-chloro-4-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   477)     6-chloro-N-(3-chloro-5-(4-chloro-3-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   478)     6-chloro-N-(3-chloro-5-(4-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   479)     6-chloro-N-(3-chloro-5-(3-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   480)     6-chloro-N-(3-chloro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   481)     6-chloro-N-(3-chloro-5-(3,4-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   482)     6-chloro-N-(3-chloro-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   483)     6-chloro-N-(3-chloro-5-(3-chloro-5-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   484)     6-chloro-N-(3-chloro-5-(3-fluoro-5-methoxyphenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   485)     5-chloro-N-(3-chloro-5-(4-chlorophenoxy)phenyl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   486)     6-chloro-N-(3-chloro-5-(cyclohexyloxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   487)     6-chloro-N-(3-chloro-5-((5-methylthiophen-2-yl)oxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   488)     4-bromo-N-(3-chloro-5-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   489)     N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   490)     6-chloro-N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   491)     N-(2-chloro-6-((6-chloropyridin-3-yl)oxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   492)     6-chloro-N-(2-chloro-6-(6-chloropyridin-3-yl)oxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   493)     N-(2-chloro-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   494)     6-chloro-N-(2-chloro-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   495)     N-(2-chloro-6-(4-(trifluoromethyl)phenoxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   496)     6-chloro-N-(2-chloro-6-(4-(trifluoromethyl)phenoxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; -   497)     N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide;     and -   498)     N-(3-chloro-5-(4-chlorophenoxy)phenyl)-6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide.

The above-listed names of the compounds are described in accordance with the nomenclature method provided by ChemBioDraw Ultra software (Version 13.0.0.3015) of PerkinElmer.

The present invention provides a pharmaceutically acceptable salt of a heterocyclic derivative represented by formula (I) above. The pharmaceutically acceptable salt should have low toxicity to humans, and should not have any negative impact on the biological activities and physicochemical properties of parent compounds. Examples of the pharmaceutically acceptable salt may include an acid addition salt between a pharmaceutically usable free acid and a basic compound represented by formula (I), an alkaline metal salt (sodium salt, etc.) and an alkaline earth metal salt (potassium salt, etc.), an organic base addition salt between an organic base and carboxylic acid represented by formula (I), amino acid addition salt, etc.

Examples of a suitable form of salts according to the present invention may be a salt with an inorganic acid or organic acid, wherein the inorganic acid may be hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, bromic acid, etc., and the organic acid may be acetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, malonic acid, phthalic acid, succinic acid, lactic acid, citric acid, gluconic acid, tartaric acid, salicylic acid, malic acid, oxalic acid, benzoic acid, embonic acid, aspartic acid, glutamic acid, etc. The organic base which may be used for the preparation of the organic base addition salt may include tris(hydroxymethyl)methylamine, dicyclohexylamine, etc. Amino acids which may be used for the preparation of amino acid addition base may include natural amino acids such as alanine, and glycine.

The salts may be prepared using a conventional method. For example, the salts may be prepared by dissolving the compound represented by formula (I) in a water-miscible solvent such as methanol, ethanol, acetone, and 1,4-dioxane, adding a free acid or a free base, and then crystallizing the resultant thereafter.

Additionally, the compounds of the present invention may have a chiral carbon center, and thus they may be present in the form of an R or S isomer, a racemic compound, an individual enantiomer or a mixture, an individual diastereomer or a mixture, and all these stereoisomers and a mixture thereof may belong to the scope of the present invention.

Additionally, the compounds of the present invention may also include a hydrate or solvate of the heterocyclic derivative represented by formula (I). The hydrate or solvate may be prepared using a known method, and they are preferred to be non-toxic and water-soluble, and in particular, they are preferably water or a hydrate or solvate having 1-5 molecules of alcoholic solvent (especially ethanol, etc.) bound thereto.

The present invention also provides a use of a compound selected from the group consisting of a heterocyclic derivative represented by formula (I) above, and a pharmaceutically acceptable salt and a stereoisomer thereof for the manufacture of a medicament for preventing or treating diseases associated with the activation of STAT3 protein.

Further, the present invention provides method for preventing or treating diseases associated with the activation of STAT3 protein in a mammal, which comprises administering a compound selected from the group consisting of a heterocyclic derivative represented by formula (I) above, and a pharmaceutically acceptable salt and a stereoisomer thereof to the mammal.

Further, the present invention provides a pharmaceutical composition for preventing or treating diseases associated with the activation of STAT3 protein, comprising a compound selected from the group consisting of a heterocyclic derivative represented by formula (I) above, and a pharmaceutically acceptable salt and a stereoisomer thereof as active ingredients.

Specifically, the diseases associated with the activation of STAT3 protein is selected from the group consisting of solid cancers, hematological or blood cancers, radio- or chemo-resistant cancers, metastatic cancers, inflammatory diseases, immunological diseases, diabetes, macular degeneration, human papillomavirus infection and tuberculosis.

More specifically, the diseases associated with the activation of STAT3 protein are selected from the group consisting of breast cancer, lung cancer, stomach cancer, prostate cancer, uterine cancer, ovarian cancer, kidney cancer, pancreatic cancer, liver cancer, colon cancer, skin cancer, head and neck cancer, thyroid cancer, osteosarcoma, acute or chronic leukemia, multiple myeloma, B- or T-cell lymphoma, non-Hodgkin's lymphoma, auto-immune diseases comprising rheumatoid arthritis, psoriasis, hepatitis, inflammatory bowel disease, Crohn's disease, diabetes, macular degeneration, human papillomavirus infection, and tuberculosis.

In particular, a heterocyclic derivative represented by formula (I) above, or a pharmaceutically acceptable salt or a stereoisomer thereof has an excellent inhibitory effect on the activation of STAT3 protein, and thus the present invention also provides a composition for the inhibition of STAT3 protein comprising the same as an active ingredient.

The pharmaceutical composition of the present invention, in addition to the heterocyclic derivative represented by formula (I) above, the pharmaceutically acceptable salt thereof, or the stereoisomer thereof, may further include as active ingredients, common and non-toxic pharmaceutically acceptable additives, for example, a carrier, an excipient, a diluent, an adjuvant, etc., to be formulated into a preparation according to a conventional method.

The pharmaceutical composition of the present invention may be formulated into various forms of preparations for oral administration such as tablets, pills, powders, capsules, syrups, or emulsions, or for parenteral administration such as intramuscular, intravenous or subcutaneous injections, etc., and preferably in the form of a preparation for oral administration.

Examples of the additives to be used in the pharmaceutical composition of the present invention may include sweeteners, binders, solvents, solubilization aids, wetting agents, emulsifiers, isotonic agents, absorbents, disintegrating agents, antioxidants, preservatives, lubricants, fillers, flavoring agents, etc. For example, they may include, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, magnesium alluminosilicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.

The pharmaceutical composition of the present invention may be formulated into a preparation for oral administration by adding additives to active ingredients, wherein the additives may include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspension agents, emulsifiers, diluents, etc.

The pharmaceutical composition of the present invention may be formulated into a preparation for injection by adding additives to the active ingredients, for example, water, a saline solution, a glucose solution, an aqueous glucose solution analog, alcohol, glycol, ether, oil, fatty acid, fatty acid ester, glyceride, surfactants, suspension agents, emulsifiers, etc.

The compound of the present invention may be administered preferably in an amount ranging from 0.1 to 2,000 mg/day based on an adult subject with 70 kg body weight. The compound of the present invention may be administered once daily or a few divided doses. The dosage of the compound of the present invention may vary depending on the health conditions, age, body weight, sex of the subject, administration route, severity of illness, etc., and the scope of the present invention will not be limited to the dose suggested above.

EXAMPLE

Hereinafter, the present invention is described more specifically by the following examples, but these are provided only for illustration purposes and the present invention is not limited thereto.

The definition of the abbreviations used in the following examples is as follows.

TABLE 1 Abbreviation Full name Al(CH₃)₃ Trimethyl aluminum AlCl₃ Aluminum chloride AcOH Acetic acid AIBN 2,2′-Azobis(2-methylpropionitrile) BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl rac-BINAP rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl BBr₃ Boron tribromide Boc₂O Di-tert-butyl dicarbonate Brine Brine is water saturated or nearly saturated with a brine salt (generally, sodium chloride) n-BuLi n-butyllithium tert-BuLi tert-butyllithium CCl₄ Carbon tetrachloride CH₃CN Acetonitrile CHCl₃ Chloroform CHBr₃ Bromoform CDCl₃ Deuterated chloroform CD₃OD Methanol-d₄ CH₂Cl₂ Dichloromethane CH₂I₂ Diiodomethane CH₃I Methyl iodide (COCl)₂ Oxalyl chloride Cs₂CO₃ Cesium carbonate CuCN Copper (I) cyanide CuI Copper (I) iodide Cu₂O Copper (I) oxide CuSO₄•5H₂O Copper(II) sulfate pentahydrate DEAD Diethyl azodicarboxylate Deoxo-Fluor Bis(2-methoxyethyl)aminosulfur trifluoride DIAD Diisopropyl azodicarboxylate DIBAL Diisobutylaluminum hydride DIPEA N,N-Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP 4-Dimethylaminopyridine DME 1,2-Dimethoxyethane DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide DMSO-d₆ Dimethylsulfoxide-d₆ EDC Ethyl-(N,N-dimethylamino)propylcarbodiimide EtOAc Ethyl acetate EtOH Ethyl alcohol Et₂O Diethyl ether Et₃N Triethylamine Et₂Zn Diethylzinc Fe Iron HATU 2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3- tetramethyluronium hexafluorophosphate HBr Hydrogen bromide HCl Hydrogen chloride H₂SO₄ Sulfuric acid n-Hex n-Hexane HMPA Hexamethylphosphoramide HNO₃ Nitric acid H₂O Water H₂O₂ Hydrogen peroxide HOBt 1-Hydroxybenzotriazole H-Gly-OEt•HCl Glycine ethyl ester hydrochloride i-Pr₂O Diisopropyl ether K₂CO₃ Potassium carbonate KMnO₄ Potassium manganate(VII) KOAc Potassium acetate KOH Potassium hydroxide K₃PO₄•H₂O Tripotassium phosphate monohydrate LiAlH₄ Lithium aluminum hydride LiOH•H₂O Lithium hydroxide, monohydrate LiOMe Lithium methoxide mCPBA meta-Chloroperoxybenzoic acid MeOH Methyl alcohol MnO₂ Manganese dioxide NaBH₃CN Sodium cyanoborohydride NBS N-Bromosuccinimide Na₂CO₃ Sodium carbonate Na₂SO₄ Sodium sulfate NaH Sodium hydride NaHCO₃ Sodium bicarbonate NaOAc Sodium acetate NaOH Sodium hydroxide NaOMe Sodium methoxide NaOt-Bu Sodium tert-butoxide NaBH₄ Sodium borohydride NaN₃ Sodium azide NaI Sodium iodide NH₄Cl Ammonium chloride NH₄OH Ammonium hydroxide NHMe₂ Dimethylamine Pd(dba)₂ Bis(dibenzylideneacetone)palladium(0) Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0) Pd₂(dba)₃•CHCl₃ Tris(dibenzylideneacetone)dipalladium(0), chloroform adduct Pd(dppf)₂Cl₂•CH₂Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]dichloro- palladium(II), dichloromethane adduct Pd(dppf)₂Cl₂ [1,1′-bis(diphenylphosphino)ferrocene]dichloro- palladium(II) Pd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium(0) Pd(OAc)₂ Palladium(II) acetate Pd(t-bu₃P)₂ Bis(tri-tert-butylphosphine)palladium(0) PCl₅ Phosphorus pentachloride PPh₃ Triphenylphosphine POCl₃ Phosphoryl chloride Ra—Ni Raney nickel (SnMe₃)₂ Hexamethylditin SOCl₂ Thionyl chloride TBAF Tetra-n-butylammonium fluoride Tf₂O Trifluoromethanesulfonic anhydride THF Tetrahydrofuran TiCl₄ Titanium tetrachloride TFA Trifluoroacetic acid Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Zn Zinc ZnI₂ Zinc iodide

Intermediate 1) Synthesis of 6-(methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (a) Synthesis of methyl 6-nitro-1H-indole-2-carboxylate 6-Nitro-1H-indole-2-carboxylic acid (100.0 mg, 0.49 mmol) was dissolved in

MeOH (2.4 mL), and SOCl₂ (100.0 μL) was slowly added. The reaction mixture was refluxed for 4 hours and concentrated under reduced pressure, and the residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=30:1) to obtain methyl 6-nitro-1H-indole-2-carboxylate (107.0 mg, 100%) as a yellow solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 12.64 (brs, 1H), 8.34 (s, 1H), 7.92 (m, 2H), 7.33 (s, 1H), 3.93 (s, 3H)

(b) Synthesis of methyl 6-amino-1H-indole-2-carboxylate

Methyl 6-nitro-1H-indole-2-carboxylate (4.3 g, 19.39 mmol) was dissolved in a mixture of THF/MeOH/H₂O (115.0 mL, 1/1/0.5 v/v), and Zn (12.7 g, 0.19 mmol) and NH₄Cl (3.1 g, 58.14 mmol) were added. The reaction mixture was ultrasonificated at 40° C. for 1 hour, filtered through Celite and concentrated under reduced pressure. The residue was recrystallized in a mixture of i-Pr₂O/MeOH/EtOAc (100.0 mL, 1/0.1/0.1 v/v) to obtain methyl 6-amino-1H-indole-2-carboxylate (3.2 g, 86%) as a yellow solid.

LC/MS (ESI+): 191 (M+1)

(c) Synthesis of methyl 6-(methylsulfonamido)-1H-indole-2-carboxylate

Methyl 6-amino-1H-indole-2-carboxylate (250.0 mg, 1.31 mmol) was dissolved in pyridine (10.0 mL), and methanesulfonyl chloride (107.0 μL, 1.38 mmol) was slowly added at 0° C. The reaction mixture was stirred at room temperature for 3 hours, extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was recrystallized in a mixture of i-Pr₂O/MeOH (100.0 mL, 1/0.1 v/v) to obtain methyl 6-(methylsulfonamido)-1H-indole-2-carboxylate (280.0 mg, 80%) as a yellow solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 11.87 (brs, 1H), 9.69 (brs, 1H), 7.60 (d, 1H, J=9.0 Hz), 7.37 (s, 1H), 7.11 (m, 1H), 6.98 (dd, 1H, J=8.4, 1.8 Hz), 3.85 (s, 3H), 2.95 (s, 3H)

(d) Synthesis of 6-(methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride

Methyl 6-(methylsulfonamido)-1H-indole-2-carboxylate (280.0 mg, 1.04 mmol) was dissolved in a mixture of THF/MeOH/H₂O (5.6 mL, 5/3/1 v/v), and LiOH.H₂O (125.0 mg, 5.22 mmol) was added. The reaction mixture was stirred at room temperature for 10 hours, concentrated under reduced pressure. The residue was diluted in H₂O (2.0 mL), acidified to pH 1-2 with 1 N HCl and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was recrystallized with a mixture of i-Pr₂O/MeOH (10.0 mL, 1/0.1 v/v) to obtain 6-(methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (136.0 mg, 45%) as an off-white solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 12.60 (brs, 1H), 11.48 (brs, 1H), 9.43 (brs, 1H), 7.36 (d, 1H, J=8.4 Hz), 7.15 (s, 1H), 6.82 (m, 1H), 6.75 (dd, 1H, J=8.4, 1.8 Hz), 2.73 (s, 3H)

Intermediate 2) Synthesis of 6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxylic acid hydrochloride (a) Synthesis of methyl 6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxylate

Methyl 6-amino-1H-indole-2-carboxylate (intermediate 1-b) (900.0 mg, 4.73 mmol) and DMAP (2.0 g, 16.60 mmol) were dissolved in CH₃CN (20.0 mL), and methylsulfamoyl chloride (644.0 mg, 4.97 mmol) was slowly added at 0° C. After refluxing for 1 hour, the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain methyl 6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxylate (902.0 mg, 64%) as a brown solid.

LC/MS ESI (+): 284 (M+1)

(b) Synthesis of 6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxylic acid hydrochloride

Methyl 6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxylate (900.0 mg, 3.18 mmol) was dissolved in a mixture of THF/MeOH/H₂O (18.0 mL, 5/10/3 v/v), and LiOH.H₂O (380.0 mg, 15.90 mmol) was added. After stirring at room temperature for 14 hours, the reaction mixture was concentrated under reduced pressure. The residue was diluted in H₂O (2.0 mL), acidified to pH 1-2 with 1 N HCl and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was recrystallized using i-Pr₂O to obtain 6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxylic acid hydrochloride (630.0 mg, 70%) as a brown solid.

LC/MS ESI (+): 270 (M+1)

Intermediate 3) Synthesis of 5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of ethyl 5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate

Ethyl 5-amino-1-benzothiophene-2-carboxylate (300.0 mg, 1.36 mmol) was dissolved in pyridine (15.0 mL), and methanesulfonyl chloride (111.0 μL, 1.38 mmol) was slowly added at 0° C. The reaction mixture was stirred at room temperature for 3 hours, extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was recrystallized using a mixture of i-Pr₂O/MeOH (100.0 mL, 1/0.1 v/v) to obtain ethyl 5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (350.0 mg, 86%) as a yellow solid.

LC/MS ESI (+): 300 (M+1)

(b) Synthesis of 5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid

Ethyl 5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (189.0 mg, 0.66 mmol) was dissolved in a mixture of THF/H₂O (6.6 mL, 2/1 v/v), and LiOH.H₂O (278.0 mg, 6.62 mmol) was added. The reaction mixture was stirred at room temperature for 10 hours, concentrated under reduced pressure. The residue was diluted in H₂O (2.0 mL) and acidified to pH 1-2 with 1 N HCl. The precipitate was filtered, washed with i-Pr₂O and dried under reduced pressure to obtain 5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (165.5 mg, 92%) as an off-white solid.

LC/MS ESI (+): 272 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 13.50 (s, 1H), 9.88 (s, 1H), 8.08 (s, 1H), 8.00 (d, 1H, J=9.0 Hz), 7.82 (d, 1H, J=1.8 Hz), 7.35 (dd, 1H, J=9.0, 1.8 Hz), 3.01 (s, 3H)

Intermediate 4) Synthesis of 5-(morpholine-4-sulfonamido)benzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 3 was repeated except for using ethyl 5-amino-1-benzothiophene-2-carboxylate (100.0 mg, 0.45 mmol) to obtain 5-(morpholine-4-sulfonamido)benzo[b]thiophene-2-carboxylic acid (60.0 mg).

LC/MS ESI (+): 343 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.40 (brs, 1H), 10.67 (s, 1H), 8.09 (s, 1H), 7.97 (d, 1H, J=8.8 Hz), 7.81 (d, 1H, J=1.9 Hz), 7.37 (dd, 1H, J=8.8, 2.1 Hz), 3.50-3.52 (m, 4H), 3.07-3.09 (m, 4H)

Intermediate 5) Synthesis of 5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 3 was repeated except for using ethyl 5-amino-1-benzothiophene-2-carboxylate (100.0 mg, 0.45 mmol) to obtain 5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxylic acid (16.0 mg).

LC/MS ESI (+): 328 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.09 (s, 1H), 8.11 (s, 1H), 8.02 (d, 1H, J=8.8 Hz), 7.86 (d, 1H, J=1.6 Hz), 7.38 (dd, 1H, J=8.8, 1.6 Hz), 3.90-4.01 (m, 2H), 3.79-3.87 (m, 2H), 3.61-3.66 (m, 1H), 2.12-2.18 (m, 2H)

Intermediate 6) Synthesis of 3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of ethyl 3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxylate

Ethyl 6-amino-3-methylbenzo[b]thiophene-2-carboxylate (300.0 mg, 1.27 mmol) was dissolved in pyridine (12.7 mL), and methanesulfonyl chloride (128.0 μL, 1.65 mmol) was slowed added at 0° C. The reaction mixture was stirred at room temperature for 1 hour, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=20:1) to obtain ethyl 3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (394.0 mg, 99%) as a white solid.

LC/MS ESI (+): 314 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 9.90 (s, 1H), 7.98 (d, 1H, J=8.8 Hz), 7.72 (m, 1H), 7.42 (dd, 1H, J=8.8, 1.8 Hz), 4.33 (q, 2H, J=7.2 Hz), 3.01 (s, 3H), 2.68 (s, 3H), 1.33 (t, 3H, J=6.9 Hz)

(b) Synthesis of 3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid

Ethyl 3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (390.0 mg, 1.24 mmol) was dissolved in a mixture of THF/H₂O (24.8 mL, 2/1 v/v), and LiOH.H₂O (261.0 mg, 6.22 mmol) was added. The reaction mixture was stirred at room temperature for 10 hours, concentrated under reduced pressure. The residue was diluted in H₂O (2.0 mL), acidified to pH 1-2 with 1 N HCl, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure to obtain 3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (354.0 mg, 100%) as a white solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 13.38 (brs, 1H), 9.87 (s, 1H), 7.96 (d, 1H, J=8.8 Hz), 7.71 (m, 1H), 7.40 (dd, 1H, J=8.8, 1.8 Hz), 3.01 (s, 3H), 2.66 (s, 3H)

Intermediate 7) Synthesis of 5-(methylsulfonamido)benzofuran-2-carboxylic acid (a) Synthesis of ethyl 5-(methylsulfonamido)benzofuran-2-carboxylate

Ethyl 5-aminobenzofuran-2-carboxylate (300.0 mg, 1.46 mmol) was dissolved in pyridine (15.0 mL), and methanesulfonyl chloride (119.0 μL, 1.38 mmol) was slowly added at 0° C. The reaction mixture was stirred at room temperature for 3 hours, extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was recrystallized using a mixture of i-Pr₂O/MeOH (100.0 mL, 1/0.1 v/v) to obtain ethyl 5-(methylsulfonamido)benzofuran-2-carboxylate (300.0 mg, 72%) as an off-white solid.

LC/MS ESI (+): 284 (M+1)

(b) Synthesis of 5-(methylsulfonamido)benzofuran-2-carboxylic acid

Ethyl 5-(methylsulfonamido)benzofuran-2-carboxylate (180.0 mg, 0.71 mmol) was dissolved in a mixture of THF/H₂O (6.6 mL, 2/1 v/v), and LiOH.H₂O (299.0 mg, 6.62 mmol) was added. The reaction mixture was stirred at room temperature for 10 hours, concentrated under reduced pressure. The residue was diluted in H₂O (2.0 mL) and acidified to pH 1-2 with 1 N HCl. The precipitate was filtered and washed with i-Pr₂O. The precipitate was dried under reduced pressure to obtain 5-(methylsulfonamido)benzofuran-2-carboxylic acid (170.0 mg, 94%) as an off-white solid.

LC/MS ESI (+): 256 (M+1)

Intermediate 8) Synthesis of 5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxylic acid (a) Synthesis of ethyl 5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxylate

Ethyl 6-amino-5-methoxy-1H-indole-2-carboxylate (100.0 mg, 0.43 mmol) was dissolved in pyridine (4.3 mL), and methanesulfonyl chloride (39.8 μL, 0.51 mmol) was slowly added at 0° C. The reaction mixture was stirred at room temperature for 1 hour, extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=20:1) to obtain ethyl 5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxylate (131.0 mg, 97%) as a white solid.

LC/MS ESI (+): 313 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.71 (s, 1H), 8.90 (brs, 1H), 7.39 (s, 1H), 7.19 (s, 1H), 7.04 (m, 1H), 4.31 (q, 2H, J=7.2 Hz), 3.83 (s, 3H), 2.91 (s, 3H), 1.32 (t, 3H, J=7.5 Hz)

(b) Synthesis of 5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxylic acid

Ethyl 5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxylate (131.0 mg, 0.42 mmol) was dissolved in a mixture of THF/H₂O (8.4 mL, 2/1 v/v), and LiOH.H₂O (88.0 mg, 2.10 mmol) was added. The reaction mixture was stirred at room temperature for 10 hours, acidified to pH 1-2 with 1 N HCl, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure to obtain 5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxylic acid (119.0 mg, 100%) as a white solid.

LC/MS ESI (+): 285 (M+1)

¹H-NMR (300 MHz, DMSO-d₆); δ 12.88 (brs, 1H), 11.59 (s, 1H), 8.83 (s, 1H), 7.38 (s, 1H), 7.20 (s, 1H), 6.98 (s, 1H), 3.83 (s, 3H), 2.91 (s, 3H)

Intermediate 9) Synthesis of 6-(methylsulfonamido)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride (a) Synthesis of 6-amino-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid

In a sealed tube, 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (500.0 mg, 2.53 mmol) was dissolved in 30% NH₄OH (15.0 mL), and CuSO₄.5H₂O (318.0 mg, 1.27 mmol) was added. The reaction mixture was refluxed at 150° C. for 48 hours, and concentrated under reduced pressure to obtain a mixture of a white solid of 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid and 6-amino-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid by 1:1.

LC/MS ESI (+): 178 (M+1)

(b) Synthesis of methyl 6-amino-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

The mixture (500.0 mg) of 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid and 6-amino-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid was dissolved in MeOH (20.0 mL), and SOCl₂ (4.0 mL) was added. The reaction mixture was refluxed at 80° C. for 19 hours and concentrated under reduced pressure to obtain a mixture of a white solid of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate and methyl 6-amino-1H-pyrrolo[2,3-b]pyridine-2-carboxylate by 1:1.

LC/MS ESI (+): 192 (M+1)

(c) Synthesis of methyl 6-(methylsulfonamido)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate

The synthesis procedure of Intermediate 6-a was repeated except for using the mixture of methyl 6-chloro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate and methyl 6-amino-1H-pyrrolo[2,3-b]pyridine-2-carboxylate to obtain methyl 6-(methylsulfonamido)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (76.0 mg, 3 step yield: 8%) as a white solid.

LC/MS ESI (+): 270 (M+1)

(d) Synthesis of 6-(methylsulfonamido)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride

The synthesis procedure of Intermediate 6-b was repeated except for using methyl 6-(methylsulfonamido)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (76.0 mg, 0.20 mmol) to obtain 6-(methylsulfonamido)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride (30.0 mg, 60%).

LC/MS ESI (+): 256 (M+1)

Intermediate 10) Synthesis of 6-(methylsulfonamido)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid hydrochloride

The synthesis procedure of Intermediate 9 was repeated except for using 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (300.0 mg) to obtain 6-(methylsulfonamido)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid hydrochloride (30.0 mg).

LC/MS ESI (+): 256 (M+1)

Intermediate 11) Synthesis of 5-(methylsulfonamido)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid hydrochloride

The synthesis procedure of Intermediate 9 was repeated except for using ethyl 5-bromo-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (200.0 mg, 0.74 mmol) to obtain 5-(methylsulfonamido)-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid hydrochloride (21.6 mg).

LC/MS ESI (+): 256 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 13.48 (brs, 1H), 12.17 (s, 1H), 9.98 (s, 1H), 8.58 (s, 1H), 7.29 (s, 1H), 7.06 (s, 1H), 3.19 (s, 3H)

Intermediate 12) Synthesis of 4-(methylsulfonamido)thiophene-2-carboxylic acid (a) Synthesis of methyl 4-(methylsulfonamido)thiophene-2-carboxylate

The synthesis procedure of Intermediate 1-c was repeated except for using methyl 4-aminothiophene-2-carboxylate (100.0 mg, 0.64 mmol) to obtain methyl 4-(methylsulfonamido)thiophene-2-carboxylate (110.0 mg, 73%).

LC/MS ESI (+): 236 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.63 (d, 1H, J=1.6 Hz), 7.31 (d, 1H, J=1.6 Hz), 6.61 (s, 1H), 3.90 (s, 3H), 3.03 (s, 3H)

(b) Synthesis of 4-(methylsulfonamido)thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 1-d was repeated except for using methyl 4-(methylsulfonamido)thiophene-2-carboxylate (110.0 mg, 0.47 mmol) to obtain 4-(methylsulfonamido)thiophene-2-carboxylic acid (95.0 mg, 91%).

¹H-NMR (400 MHz, MeOH-d₄): δ 7.59 (d, 1H, J=1.7 Hz), 7.30 (d, 1H, J=1.7 Hz), 2.97 (s, 3H)

Intermediate 13) Synthesis of 6-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of methyl 6-nitrobenzo[b]thiophene-2-carboxylate

2,4-Dinitrobenzaldehyde (1.2 g, 5.96 mmol) and Et₃N (2.0 mL, 14.40 mmol) were dissolved in DMSO (7.0 mL), and methyl-2-mercaptoacetate (0.6 mL, 6.00 mmol) was slowly added at room temperature. After stirring for 12 hours, the reaction mixture was heated at 110° C. for 2 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was washed with Et₂O to obtain methyl 6-nitrobenzo[b]thiophene-2-carboxylate (1.1 g, 78%) as a yellow solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 9.18 (s, 1H), 8.38 (s, 1H), 8.26-8.27 (m, 2H), 3.93 (s, 3H)

(b) Synthesis of methyl 6-aminobenzo[b]thiophene-2-carboxylate

Methyl 6-nitrobenzo[b]thiophene-2-carboxylate (500.0 mg, 2.11 mmol), Zn (2.1 g, 31.60 mmol), and NH₄Cl (564.0 mg, 10.60 mmol) were dissolved in a mixture of THF/MeOH/H₂O (42.0 mL, 1/0.5/0.5 v/v). The reaction mixture was ultrasonificated for 2 hours, filtered through Celite and concentrated under reduced pressure to obtain methyl 6-aminobenzo[b]thiophene-2-carboxylate (437.0 mg) as a white solid without purification.

LC/MS ESI (+): 208 (M+1)

(c) Synthesis of methyl 6-(methylsulfonamido)benzo[b]thiophene-2-carboxylate

Crude methyl 6-aminobenzo[b]thiophene-2-carboxylate (437.0 mg) was dissolved in pyridine (21.0 mL), and methanesulfonyl chloride (213.0 μL, 2.74 mmol) was slowly added at room temperature. After stirring for 2 hours, the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=1:1) to obtain methyl 6-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (272.0 mg, 2 step yield: 45%) as a yellow solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 10.18 (s, 1H), 8.14 (s, 1H), 7.97 (d, 1H, J=8.8 Hz), 7.83 (s, 1H), 7.30 (dd, 1H, J=9.2, 1.5 Hz), 3.87 (s, 3H), 3.09 (s, 3H)

(d) Synthesis of 6-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid

Methyl 6-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (270.0 mg, 0.95 mmol) and LiOH.H₂O (199.0 mg, 4.73 mmol) were dissolved in a mixture of THF/H₂O (9.5 mL, 4/1 v/v), followed by stirring at room temperature for 24 hours. The reaction mixture was acidified to pH 1-2 with 1 N HCl and then extracted with EtOAc. The organic extract was dried over anhydrous Na₂SO₄ and filtered to obtain 6-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (257.0 mg, 100%) as a white solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 13.30 (brs, 1H), 10.11 (s, 1H), 8.03 (s, 1H), 7.94 (d, 1H, J=8.8 Hz), 7.80 (s, 1H), 7.29 (dd, 1H, J=8.8, 2.3 Hz), 3.07 (s, 3H)

Intermediate 14) Synthesis of 6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of methyl 6-fluoro-5-nitrobenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 13-a was repeated except for using 2,4-difluoro-5-nitrobenzaldehyde (5.0 g, 26.70 mmol) to obtain methyl 6-fluoro-5-nitrobenzo[b]thiophene-2-carboxylate mixture (1.6 g).

¹H-NMR (300 MHz, CDCl₃): δ 8.62 (d, 1H, J=7.2 Hz), 8.13 (s, 1H), 7.77 (d, 1H, J=10.4 Hz), 3.99 (s, 3H)

(b) Synthesis of methyl 5-amino-6-fluorobenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 13-b was repeated except for using methyl 6-fluoro-5-nitrobenzo[b]thiophene-2-carboxylate mixture (1.6 g) to obtain methyl 5-amino-6-fluorobenzo[b]thiophene-2-carboxylate (853.0 mg, 2 step yield: 14%).

LC/MS ESI (+): 226 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 7.86 (s, 1H), 7.45 (d, 1H, J=10.8 Hz), 7.21 (d, 1H, J=8.4 Hz), 3.92 (s, 3H), 3.86 (s, 2H)

(c) Synthesis of methyl 6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 13-c was repeated except for using methyl 5-amino-6-fluorobenzo[b]thiophene-2-carboxylate (530.0 mg, 2.35 mmol) to obtain methyl 6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (663.0 mg, 93%).

LC/MS ESI (+): 304 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 9.78 (s, 1H), 8.23 (s, 1H), 8.12 (d, 1H, J=10.3 Hz), 8.06 (d, 1H, J=7.7 Hz), 3.89 (s, 3H), 3.06 (s, 3H)

(d) Synthesis of 6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 13-d was repeated except for using methyl 6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (134.6 mg, 0.44 mmol) to obtain 6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (118.0 mg, 92%).

LC/MS ESI (+): 290 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.56 (brs, 1H), 9.75 (s, 1H), 8.11 (s, 1H), 8.08 (d, 1H, J=10.4 Hz), 8.02 (d, 1H, J=7.7 Hz), 3.06 (s, 3H)

Intermediate 15) Synthesis of 6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of methyl 6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxylate

Methyl 6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (intermediate 14-c) (663.0 mg, 2.19 mmol) was dissolved in anhydrous DMF (22.0 mL), and CH₃I (272.0 μL, 4.37 mmol) and K₂CO₃ (906.4 mg, 6.56 mmol) were added at room temperature. The reaction mixture was heated at 60° C. for 14 hours and cooled to room temperature, followed by adding water and extracting with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain methyl 6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxylate (672.8 mg, 97%) as an off-white solid.

LC/MS ESI (+): 318 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.22 (d, 1H, J=7.6 Hz), 8.20 (s, 1H), 8.16 (d, 1H, J=10.6 Hz), 3.89 (s, 3H), 3.26 (s, 3H), 3.12 (s, 3H)

(b) Synthesis of 6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 13-d was repeated except for using methyl 6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxylate (672.8 mg, 2.12 mmol) to obtain 6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxylic acid (596.8 mg, 93%).

LC/MS ESI (+): 304 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 13.65 (brs, 1H), 8.20 (d, 1H, J=7.5 Hz), 8.20 (d, 1H, J=10.5 Hz), 8.08 (s, 1H), 3.26 (s, 3H), 3.12 (s, 3H)

Intermediate 16) Synthesis of 4-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 13 was repeated except for using 2,6-difluoro-3-nitrobenzaldehyde (300.0 mg, 1.60 mmol) to obtain 4-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (14.7 mg).

LC/MS ESI (+): 290 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 13.83 (brs, 1H), 9.77 (s, 1H), 8.03 (m, 1H), 7.88 (d, 1H, J=8.4 Hz), 7.48-7.50 (m, 1H), 3.04 (s, 3H)

Intermediate 17) Synthesis of 5-(methylsulfonamido)-4-morpholinobenzo[b]thiophene-2-carboxylic acid hydrochloride (a) Synthesis of methyl 4-fluoro-5-nitrobenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 13-a was repeated except for using 2,6-difluoro-3-nitrobenzaldehyde (300.0 mg, 1.60 mmol) to obtain regioisomers (84.0 mg) including methyl 4-fluoro-5-nitrobenzo[b]thiophene-2-carboxylate.

¹H-NMR (300 MHz, CDCl₃): δ 8.30 (s, 1H), 8.13-8.17 (m, 1H), 7.74 (d, 1H, J=8.8 Hz), 4.00 (s, 3H)

(b) Synthesis of methyl 4-morpholino-5-nitrobenzo[b]thiophene-2-carboxylate

The regioisomers of methyl 4-fluoro-5-nitrobenzo[b]thiophene-2-carboxylate (82.0 mg, 0.32 mmol), morpholine (55.5 μL, 0.64 mmol), and K₂CO₃ (88.7 mg, 0.64 mmol) were dissolved in DMSO (2.6 mL). The reaction mixture was heated at 100° C. for 5 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1), to obtain methyl 4-morpholino-5-nitrobenzo[b]thiophene-2-carboxylate (20.5 mg, 2 step yield: 4%) as a yellow solid.

LC/MS ESI (+): 323 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 8.24 (s, 1H), 7.70 (d, 1H, J=8.8 Hz), 7.60 (d, 1H, J=8.8 Hz), 3.99 (s, 3H), 3.30-3.90 (m, 4H), 3.28-3.30 (m, 4H)

(c) Synthesis of methyl 5-amino-4-morpholinobenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 13-b was repeated except for using methyl 4-morpholino-5-nitrobenzo[b]thiophene-2-carboxylate (19.0 mg, 0.06 mmol) to obtain methyl 5-amino-4-morpholinobenzo[b]thiophene-2-carboxylate (22.0 mg, quant.).

LC/MS ESI (+): 293 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 8.25 (s, 1H), 7.50 (d, 1H, J=8.8 Hz), 7.00 (d, 1H, J=8.4 Hz), 4.36 (brs, 2H), 3.97-4.03 (m, 2H), 3.95 (s, 3H), 3.76-3.82 (m, 2H), 3.55-3.62 (m, 2H), 2.83-2.86 (m, 2H)

(d) Synthesis of methyl 5-(methylsulfonamido)-4-morpholinobenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 13-c was repeated except for using methyl 5-amino-4-morpholinobenzo[b]thiophene-2-carboxylate (20.0 mg, 0.07 mmol) to obtain methyl 5-(methylsulfonamido)-4-morpholinobenzo[b]thiophene-2-carboxylate (16.8 mg, 66%).

LC/MS ESI (+): 371 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 8.33 (s, 1H), 8.31 (s, 1H), 7.77 (s, 2H), 4.02-4.07 (m, 2H), 3.98 (s, 3H), 3.81-3.85 (m, 2H), 3.66-3.69 (m, 2H), 3.05 (s, 3H), 2.73-2.77 (m, 2H)

(e) Synthesis of 5-(methylsulfonamido)-4-morpholinobenzo[b]thiophene-2-carboxylic acid hydrochloride

The synthesis procedure of Intermediate 13-d was repeated except for using methyl 5-(methylsulfonamido)-4-morpholinobenzo[b]thiophene-2-carboxylate (15.0 mg, 0.04 mmol) to obtain 5-(methylsulfonamido)-4-morpholinobenzo[b]thiophene-2-carboxylic acid hydrochloride (10.2 mg, 71%).

LC/MS ESI (+): 357 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 13.68 (brs, 1H), 8.84 (s, 1H), 8.05 (brs, 1H), 7.83 (d, 1H, J=8.8 Hz), 7.50 (d, 1H, J=8.8 Hz), 3.80-3.82 (m, 4H), 3.18-3.20 (m, 4H), 3.07 (s, 3H)

Intermediate 18) Synthesis of 5-(methylsulfonamido)thieno[3,2-b]pyridine-2-carboxylic acid hydrochloride (a) Synthesis of methyl 5-bromothieno[3,2-b]pyridine-2-carboxylate

The synthesis procedure of Intermediate 13-a was repeated except for using 6-bromo-3-fluoropicolinaldehyde (300.0 mg, 1.47 mmol) to obtain methyl 5-bromothieno[3,2-b]pyridine-2-carboxylate (368.0 mg, 92%).

LC/MS ESI (+): 272 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 8.57 (d, 1H, J=8.8 Hz), 8.20 (s, 1H), 7.75 (d, 1H, J=8.4 Hz), 3.93 (s, 3H)

(b) Synthesis of 5-bromothieno[3,2-b]pyridine-2-carboxylic acid

The synthesis procedure of Intermediate 13-d was repeated except for using methyl 5-bromothieno[3,2-b]pyridine-2-carboxylate (368.0 mg, 1.35 mmol) to obtain 5-bromothieno[3,2-b]pyridine-2-carboxylic acid without purification.

LC/MS ESI (+): 258 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 8.53 (d, 1H, J=8.8 Hz), 8.10 (s, 1H), 7.72 (d, 1H, J=8.4 Hz)

(c) Synthesis of 5-aminothieno[3,2-b]pyridine-2-carboxylic acid

The synthesis procedure of Intermediate 9-a was repeated except for using 5-bromothieno[3,2-b]pyridine-2-carboxylic acid to obtain 5-aminothieno[3,2-b]pyridine-2-carboxylic acid without purification.

LC/MS ESI (+): 195 (M+1)

(d) Synthesis of methyl 5-aminothieno[3,2-b]pyridine-2-carboxylate

The synthesis procedure of Intermediate 9-b was repeated except for using 5-aminothieno[3,2-b]pyridine-2-carboxylic acid to obtain methyl 5-aminothieno[3,2-b]pyridine-2-carboxylate (259.0 mg, 3 step yield: 92%).

LC/MS ESI (+): 209 (M+1)

(e) Synthesis of methyl 5-(methylsulfonamido)thieno[3,2-b]pyridine-2-carboxylate

The synthesis procedure of Intermediate 9-c was repeated except for using methyl 5-aminothieno[3,2-b]pyridine-2-carboxylate (288.0 mg, 1.38 mmol) to obtain methyl 5-(methylsulfonamido)thieno[3,2-b]pyridine-2-carboxylate (159.0 mg, 40%).

¹H-NMR (300 MHz, DMSO-d₆): δ 10.93 (s, 1H), 8.48 (d, 1H, J=8.8 Hz), 8.06 (s, 1H), 7.12 (d, 1H, J=8.8 Hz), 3.92 (s, 3H), 3.42 (s, 3H)

(f) Synthesis of 5-(methylsulfonamido)thieno[3,2-b]pyridine-2-carboxylic acid hydrochloride

The synthesis procedure of Intermediate 9-d was repeated except for using methyl 5-(methylsulfonamido)thieno[3,2-b]pyridine-2-carboxylate (159.0 mg, 0.56 mmol) to obtain 5-(methylsulfonamido)thieno[3,2-b]pyridine-2-carboxylic acid hydrochloride (93.5 mg, 54%).

LC/MS ESI (+): 273 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 13.75 (brs, 1H), 10.87 (s, 1H), 8.45 (d, 1H, J=8.8 Hz), 7.95 (s, 1H), 7.09 (d, 1H, J=8.8 Hz), 3.41 (s, 3H)

Intermediate 19) Synthesis of 5-(methylsulfonamido)thieno[2,3-c]pyridine-2-carboxylic acid hydrochloride

The synthesis procedure of Intermediate 18 was repeated except for using 2-chloro-5-fluoroisonicotinaldehyde (500.0 mg, 3.13 mmol) to obtain 5-(methylsulfonamido)thieno[2,3-c]pyridine-2-carboxylic acid hydrochloride (94.0 mg).

LC/MS ESI (+): 273 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 13.93 (brs, 1H), 10.58 (brs, 1H), 9.09 (s, ¹H), 8.11 (s, 1H), 7.55 (s, 1H), 3.30 (s, 3H)

Intermediate 20) Synthesis of 5-(methylsulfonamido)thieno[2,3-b]pyridine-2-carboxylic acid (a) Synthesis of methyl thieno[2,3-b]pyridine-2-carboxylate

2-Chloronicotinaldehyde (300.0 mg, 2.12 mmol) was dissolved in anhydrous DMF (2.1 mL) and H₂O (210.0 μL), and methyl-2-mercaptoacetate (0.2 mL, 2.37 mmol) and K₂CO₃ (327.0 mg, 2.37 mmol) were slowly added at room temperature. The reaction mixture was heated at 35° C. for 12 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:5) to obtain methyl thieno[2,3-b]pyridine-2-carboxylate (288.0 mg, 70%) as an off-white oil.

LC/MS ESI (+): 194 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.70 (dd, 1H, J=4.8, 1.6 Hz), 8.17 (dd, 1H, J=8.4, 1.6 Hz), 8.02 (s, 1H), 7.38 (dd, 1H, J=8.0, 4.8 Hz), 3.98 (s, 3H)

(b) Synthesis of 2-(methoxycarbonyl)thieno[2,3-b]pyridine 7-oxide

Methyl thieno[2,3-b]pyridine-2-carboxylate (112.0 mg, 0.58 mmol) was dissolved in 35% H₂O₂ (190 pt) and AcOH (170.0 μL), and the reaction temperature was raised to 55° C. The reaction mixture was heated for 2 hours, water was added to quench the reaction, extracted with CH₂Cl₂. The reaction mixture was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain 2-(methoxycarbonyl)thieno[2,3-b]pyridine 7-oxide (80.0 mg, 66%) as a white solid.

LC/MS ESI (+): 210 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.40 (d, 1H, J=6.0 Hz), 8.05 (s, 1H), 7.81 (d, 1H, J=8.4 Hz), 7.39 (dd, 1H, J=8.0, 6.4 Hz), 3.99 (s, 3H)

(c) Synthesis of 2-(methoxycarbonyl)-5-nitrothieno[2,3-b]pyridine 7-oxide

2-(Methoxycarbonyl)thieno[2,3-b]pyridine 7-oxide (1.5 g, 7.21 mmol) was dissolved in AcOH (9.8 mL), and HNO₃ (430.0 μL 6.85 mmol) was slowly added. The reaction mixture was heated at 120° C. for 8 hours, cooled to room temperature. And the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:3) to obtain 2-(methoxycarbonyl)-5-nitrothieno[2,3-b]pyridine 7-oxide (478.0 mg, 26%) as a white solid.

LC/MS ESI (+): 255 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 9.20 (d, 1H, J=1.6 Hz), 8.61 (d, 1H, J=1.6 Hz), 8.18 (s, 1H), 4.02 (s, 3H)

(d) Synthesis of methyl 5-aminothieno[2,3-b]pyridine-2-carboxylate

2-(Methoxycarbonyl)-5-nitrothieno[2,3-b]pyridine 7-oxide (478.0 mg, 1.88 mmol) was dissolved in THF, (40.0 mL). Under an atmosphere of hydrogen gas, Ra—Ni was added, and the reaction mixture was stirred at room temperature for 12 hours, filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain methyl 5-aminothieno[2,3-b]pyridine-2-carboxylate (175.0 mg, 45%) as an off-white oil.

LC/MS ESI (+): 209 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.25 (brs, 1H), 7.84 (s, 1H), 7.38 (d, 1H, J=2.4 Hz), 3.95 (s, 3H), 3.80 (brs, 2H)

(e) Synthesis of methyl 5-(methylsulfonamido)thieno[2,3-b]pyridine-2-carboxylate

The synthesis procedure of Intermediate 13-c was repeated except for using methyl 5-aminothieno[2,3-b]pyridine-2-carboxylate (175.0 mg, 0.84 mmol) to obtain methyl 5-(methylsulfonamido)thieno[2,3-b]pyridine-2-carboxylate (234.0 mg, 93%).

LC/MS ESI (+): 287 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.51 (d, 1H, J=2.4 Hz), 8.19 (d, 1H, J=2.4 Hz), 7.99 (s, 1H), 5.03 (s, 1H), 3.98 (s, 3H), 3.07 (s, 3H)

(f) Synthesis of 5-(methylsulfonamido)thieno[2,3-b]pyridine-2-carboxylic acid

The synthesis procedure of Intermediate 13-d was repeated except for using methyl 5-(methylsulfonamido)thieno[2,3-b]pyridine-2-carboxylate (234.0 mg, 0.82 mmol) to obtain 5-(methylsulfonamido)thieno[2,3-b]pyridine-2-carboxylic acid (188.0 mg, 74%).

LC/MS ESI (+): 273 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 10.17 (s, 1H) 8.56 (d, 1H, J=2.4 Hz), 8.25 (d, 1H, J=2.4 Hz), 8.14 (s, 1H), 3.09 (s, 3H)

Intermediate 21) Synthesis of 6-nitrobenzo[d]thiazole-2-carboxylic acid

A mixture of 2-methyl-6-nitrobenzo[d]thiazole (50.0 mg, 0.26 mmol), KMnO₄ (81.0 mg, 0.51 mmol), and H₂O (1.0 mL) was heated at 105° C. for 1 hour, and KMnO₄ (81.0 mg, 0.51 mmol) was added twice with time interval of 1 hour, followed by stirring for 2 hours. The reaction temperature was cooled to room temperature, and the reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain 6-nitrobenzo[d]thiazole-2-carboxylic acid (40.0 mg, 70%) as a brown solid.

LC/MS ESI (+): 225 (M+1)

Intermediate 22) Synthesis of 5-nitro-1H-benzo[d]imidazole-2-carboxylic acid

4-Nitrobenzene-1,2-diamine (2.0 g, 13.1 mmol) was dissolved in AcOH (40.0 mL), and methyl 2,2,2-trichloroacetimidate (1.8 mL, 14.4 mmol), NH₄Cl (310.0 mg, 5.88 mmol) and DIPEA (2.1 mL, 11.8 mmol) were added at 0° C., followed by stirring at room temperature for 2 hours. The reaction mixture was extracted using CH₂Cl₂, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was dissolved in THF (30.0 mL), and 1 N NaOH aqueous solution (100.0 mL) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was neutralized by adding 1 N HCl aqueous solution (pH 7), and the precipitate was filtered and washed with water to obtain 5-nitro-1H-benzo[d]imidazole-2-carboxylic acid (820.0 mg, 30%) as a white solid.

LC/MS ESI (+): 208 (M+1)

Intermediate 23) Synthesis of 6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (a) Synthesis of ethyl 6-nitroimidazo[1,2-a]pyridine-2-carboxylate

5-Nitropyridine-2-amine (1.5 g, 10.80 mmol) and ethyl 3-bromo-2-oxopropanoate (1.6 mL, 13.00 mmol) were dissolved in EtOH (15.0 mL), followed by refluxing for 16 hours. After completing the reaction, the reaction mixture was filtered to obtain a pale yellow solid. The filtrate was extracted with EtOAc, washed with sat. NaHCO₃ aqueous solution and brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain ethyl 6-nitroimidazo[1,2-a]pyridine-2-carboxylate (2.3 g, 90%) as a yellow solid.

LC/MS ESI (+): 236 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 9.30 (s, 1H), 8.38 (s, 1H), 8.06 (d, 1H, J=10.0 Hz), 7.84 (d, 1H, J=10.4 Hz), 4.50 (q, 2H, J=7.2 Hz), 1.46 (t, 3H, J=7.2 Hz)

(b) Synthesis of methyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate

The synthesis procedure of Intermediate 13-b was repeated except for using ethyl 6-nitroimidazo[1,2-a]pyridine-2-carboxylate (300.0 mg, 1.28 mmol) to obtain methyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate (67.1 mg, 27%).

LC/MS ESI (+): 192 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 8.02 (s, 1H), 7.54 (s, 1H), 7.51 (d, 1H, J=9.6 Hz), 6.87 (d, 1H, J=9.6 Hz), 3.96 (s, 3H), 3.53 (brs, 2H)

(c) Synthesis of methyl 6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxylate

The synthesis procedure of Intermediate 13-c was repeated except for using methyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate (67.0 mg, 0.35 mmol) to obtain methyl 6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxylate (72.4 mg, 77%).

LC/MS ESI (+): 270 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 9.82 (s, 1H), 8.60 (s, 1H), 8.50 (s, 1H), 7.62 (d, 1H, J=9.2 Hz), 7.24 (d, 1H, J=9.6 Hz), 3.82 (s, 3H), 3.04 (s, 3H)

(d) Synthesis of 6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride

The synthesis procedure of Intermediate 13-d was repeated except for using methyl 6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxylate (71.0 mg, 0.26 mmol) to obtain 6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (48.5 mg, 63%).

LC/MS ESI (+): 256 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 9.81 (s, 1H), 8.55 (s, 1H), 8.51 (s, 1H), 7.63 (d, 1H, J=9.6 Hz), 7.24 (d, 1H, J=9.6 Hz), 3.05 (s, 3H)

Intermediate 24) Synthesis of 5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (a) Synthesis of tert-butyl 4-chloro-5-formyl-3,6-dihydropyridine-1(2H)-carboxylate

DMF (387.0 μL, 5.02 mmol) was cooled to 0° C., and POCl₃ (374.0 μL, 4.02 mmol) was slowly added. The resultant was diluted with CH₂Cl₂ (1.0 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled again to 0° C., and a solution of tert-butyl 4-oxopiperidine-1-carboxylate (500.0 mg, 2.51 mmol) in CH₂Cl₂ (5.0 mL) was slowly added. After stirring at room temperature for 2 hours, the reaction mixture was poured into the solution of NaOAc in ice water. The reaction mixture was extracted again with CH₂Cl₂, washed with distilled water, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was not purified to obtain tert-butyl 4-chloro-5-formyl-3,6-dihydropyridine-1(2H)-carboxylate as a colorless liquid.

(b) Synthesis of 5-(tert-butyl) 2-methyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate

The synthesis procedure of Intermediate 13-a was repeated except for using tert-butyl 4-chloro-5-formyl-3,6-dihydropyridine-1(2H)-carboxylate to obtain 5-(tert-butyl) 2-methyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (165.0 mg, 2 step yield: 22%).

¹H-NMR (300 MHz, CDCl₃): δ 7.50 (s, 1H), 4.49 (s, 2H), 3.87 (s, 3H), 3.73 (m, 2H), 2.87 (m, 2H), 1.49 (s, 9H)

(c) Synthesis of methyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

5-(tert-Butyl) 2-methyl 6,7-dihydrothieno[3,2-c]pyridine-2,5(4H)-dicarboxylate (163.0 mg, 0.55 mmol) was dissolved in CH₂Cl₂ (2.7 mL), and TFA (0.5 mL) was slowly added, followed by stirring at room temperature for 3 hours. The reaction mixture was extracted with EtOAc, washed with sat. NaHCO₃ aqueous solution and brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was dried to obtain methyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (96.0 mg, 89%) as a yellow solid.

LC/MS ESI (+): 198 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 7.45 (s, 1H), 3.93 (s, 2H), 3.86 (s, 3H), 3.16-3.19 (m, 2H), 2.83-2.88 (m, 2H), 1.88 (brs, 1H)

(d) Synthesis of methyl 5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

The synthesis procedure of Intermediate 13-c was repeated except for using methyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (94.0 mg, 0.48 mmol) to obtain methyl 5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-e]pyridine-2-carboxylate (92.6 mg, 71%).

LC/MS ESI (+): 276 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 7.49 (s, 1H), 4.40 (s, 2H), 3.88 (s, 3H), 3.63-3.65 (m, 2H), 3.01-3.03 (m, 2H), 2.87 (s, 3H)

(e) Synthesis of 5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid

The synthesis procedure of Intermediate 13-d was repeated except for using methyl 5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (91.0 mg, 0.33 mmol) to obtain 5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (80.7 mg, 94%).

LC/MS ESI (+): 262 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 13.03 (s, 1H), 7.56 (s, 1H), 4.32 (s, 2H), 3.49-3.51 (m, 2H), 2.97-2.99 (m, 5H)

Intermediate 25) Synthesis of 5-(methylsulfonamido)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (a) Synthesis of ethyl 5-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

Ethyl 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (340.0 mg, 1.61 mmol) was dissolved in a mixture of EtOH/H₂O (6.0 mL/12.0 mL), and aminosulfuric acid (182.0 mg, 1.61 mmol) and K₂CO₃ (444.8 mg, 3.22 mmol) were added, followed by stirring at room temperature for 13 hours. EtOH was evaporated under reduced pressure. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH₂Cl₂:MeOH=9:1) to obtain ethyl 5-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (95.9 mg, 26%) as a yellow liquid.

LC/MS ESI (+): 227 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 7.50 (s, 1H), 4.25 (q, 2H, J=7.1 Hz), 3.73 (brs, 2H), 3.57 (s, 2H), 2.82-2.91 (m, 4H), 1.27 (t, 3H, J=7.1 Hz)

(b) Synthesis of ethyl 5-(methylsulfonamido)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate

The synthesis procedure of Intermediate 6-a was repeated except for using ethyl 5-amino-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (95.0 mg, 0.42 mmol) to obtain ethyl 5-(methylsulfonamido)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (53.0 mg, 42%).

LC/MS ESI (+): 305 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.56 (s, 1H), 7.54 (s, 1H), 4.26 (q, 2H, J=7.1 Hz), 3.92 (s, 2H), 3.11-3.15 (m, 2H), 2.96-3.00 (m, 5H), 1.27 (t, 3H, J=7.1 Hz)

(c) Synthesis of 5-(methylsulfonamido)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid

The synthesis procedure of Intermediate 6-b was repeated except for using ethyl 5-(methylsulfonamido)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylate (53.0 mg, 0.17 mmol) to obtain 5-(methylsulfonamido)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (39.0 mg, 81%).

LC/MS ESI (+): 277 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 12.95 (brs, 1H), 8.55 (s, 1H), 7.44 (s, 1H), 3.90 (s, 2H), 3.10-3.14 (m, 2H), 2.96-2.97 (m, 5H)

Intermediate 26) Synthesis of 6-chloro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of methyl 6-chloro-5-nitrobenzo[b]thiophene-2-carboxylate

4-Chloro-2-fluoro-5-nitrobenzaldehyde (9.6 g, 47.16 mmol) was dissolved in anhydrous DMF (100.0 mL), and methyl 2-mercaptoacetate (4.0 mL, 44.73 mmol) and K₂CO₃ (13.0 g, 94.06 mmol) were added, followed by stirring at room temperature for 3 hours and heated at 50° C. for 2 hours. The reaction mixture was poured into ice water, and a brown solid was filtered and extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain methyl 6-chloro-5-nitrobenzo[b]thiophene-2-carboxylate (10.2 g) as a yellow compound without purification.

(b) Synthesis of methyl 5-amino-6-chlorobenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 13-b was repeated except for using crude methyl 6-chloro-5-nitrobenzo[b]thiophene-2-carboxylate (10.2 g) to obtain methyl 5-amino-6-chlorobenzo[b]thiophene-2-carboxylate (9.0 g, 2 step yield: 79%).

¹H-NMR (400 MHz, DMSO-d₆): δ 7.98 (s, 1H), 7.96 (s, 1H), 7.30 (s, 1H), 5.49 (brs, 2H), 3.85 (s, 3H)

(c) Synthesis of methyl 6-chloro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 6-a was repeated except for using methyl 5-amino-6-chlorobenzo[b]thiophene-2-carboxylate (4.0 g, 16.55 mmol) to obtain methyl 6-chloro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (3.2 g, 60%).

¹H-NMR (400 MHz, DMSO-d₆): δ 9.62 (s, 1H), 8.37 (s, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 3.90 (s, 3H), 3.07 (s, 3H).

(d) Synthesis of 6-chloro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 6-b was repeated except for using methyl 6-chloro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (3.2 g, 9.85 mmol) to obtain 6-chloro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (3.0 g, 100%).

¹H-NMR (400 MHz, DMSO-d₆): δ 13.62 (brs, 1H), 9.61 (s, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 3.07 (s, 3H).

Intermediate 27) Synthesis of 3-hydroxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of methyl 3-hydroxy-5-nitrobenzo[b]thiophene-2-carboxylate

Methyl 2-chloro-5-nitrobenzoate (1.0 g, 4.64 mmol) was dissolved in anhydrous DMF (23.0 mL), and methyl 2-mercaptoacetate (390.0 mg, 4.41 mmol) and K₂CO₃ (1920.0 mg, 13.89 mmol) were added, followed by heating at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1), CH₂Cl₂ (10.0 mL) was added and stirred for 10 minutes. Insoluble solid was filtered to obtain methyl 3-hydroxy-5-nitrobenzo[b]thiophene-2-carboxylate (1.2 g, 97%) as a brown solid.

¹H-NMR (400 MHz, DMSO-d₆): δ 8.33 (s, 1H), 8.06 (d, 1H, J=8.7 Hz), 7.75 (d, 1H, J=8.7 Hz), 3.59 (s, 3H)

(b) Synthesis of methyl 5-amino-3-hydroxybenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 13-b was repeated except for using methyl 3-hydroxy-5-nitrobenzo[b]thiophene-2-carboxylate (160.0 mg, 0.64 mmol) to obtain methyl 5-amino-3-hydroxybenzo[b]thiophene-2-carboxylate (220.0 mg, 100%).

LC/MS ESI (+): 224 (M+1)

(c) Synthesis of methyl 3-hydroxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 6-a was repeated except for using methyl 5-amino-3-hydroxybenzo[b]thiophene-2-carboxylate (50.0 mg, 0.24 mmol) to obtain methyl 3-hydroxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (70.0 mg, 97%).

¹H-NMR (400 MHz, DMSO-d₆): δ 10.57 (brs, 1H), 9.93 (s, 1H), 7.89 (d, 1H, J=8.7 Hz), 7.41 (dd, 1H, J=8.7, 2.1 Hz), 3.85 (s, 3H), 3.00 (s, 3H)

(d) Synthesis of 3-hydroxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 6-b was repeated except for using methyl 3-hydroxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (57.0 mg, 0.19 mmol) to obtain 3-hydroxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (35.0 mg, 61%) as a yellow solid.

LC/MS ESI (+): 288 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.60 (brs, 1H), 9.92 (s, 1H), 7.90 (d, 1H, J=8.7 Hz), 7.71 (d, 1H, J=1.9 Hz), 7.42 (dd, 1H, J=8.7, 2.1 Hz), 3.01 (s, 3H)

Intermediate 28) Synthesis of 5-chloro-6-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of 1-bromo-4-(bromomethyl)-2-chloro-5-fluorobenzene

1-Bromo-2-chloro-5-fluoro-4-methylbenzene (1.0 g, 4.48 mmol) was dissolved in 1,2-dichloroethane (45.0 mL), and NBS (955.8 mg, 4.48 mmol) and AIBN (73.6 mg, 0.45 mmol) were added, followed by heating at 90° C. for 15 hours. The reaction mixture was extracted with CH₂Cl₂, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 1-bromo-4-(bromomethyl)-2-chloro-5-fluorobenzene (880.0 mg, 65%) as a colorless liquid.

¹H-NMR (400 MHz, CDCl₃): δ 7.51 (d, 1H, J=7.1 Hz), 7.40 (d, 1H, J=8.8 Hz), 4.42 (s, 2H)

(b) Synthesis of 4-bromo-5-chloro-2-fluorobenzaldehyde

1-Bromo-4-(bromomethyl)-2-chloro-5-fluorobenzene (780.0 mg, 2.58 mmol) was dissolved in anhydrous CH₃CN (25.8 mL), and N-methylmorpholine-N-oxide (604.5 mg, 5.16 mmol) and molecular sieve (2.0 g, 4 Å) were added, followed by stirring at room temperature for 5 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 4-bromo-5-chloro-2-fluorobenzaldehyde (404.8 mg, 66%) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ 10.26 (s, 1H), 7.94 (d, 1H, J=6.6 Hz), 7.54 (d, 1H, J=9.2 Hz)

(c) Synthesis of methyl 6-bromo-5-chlorobenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 26-a was repeated except for using 4-bromo-5-chloro-2-fluorobenzaldehyde (404.8 mg, 1.71 mmol) to obtain methyl 6-bromo-5-chlorobenzo[b]thiophene-2-carboxylate (311.7 mg, 60%).

¹H-NMR (400 MHz, CDCl₃): δ 8.14 (s, 1H), 7.97 (s, 1H), 7.94 (s, 1H), 3.95 (s, 3H)

(d) Synthesis of methyl 5-chloro-6-(methylsulfonamido)benzo[b]thiophene-2-carboxylate

Methyl 6-bromo-5-chlorobenzo[b]thiophene-2-carboxylate (311.7 mg, 1.02 mmol) and methanesulfonamide (145.5 mg, 1.53 mmol) were dissolved in 1,4-dioxane (20.0 mL), and Pd₂(bda)₃(0) (93.4 mg, 0.10 mmol), Xantphos (177.1 mg, 0.31 mmol) and Cs₂CO₃ (664.7 mg, 2.04 mmol) were added, followed by refluxing at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1), followed by adding EtOH (5.0 mL) and stirring for 10 minutes. The resultant was filtered to obtain methyl 5-chloro-6-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (165.7 mg, 51%) as a yellow solid.

LC/MS ESI (+): 320 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 9.70 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 8.14 (s, 1H), 3.89 (s, 3H), 3.11 (s, 3H)

(e) Synthesis of 5-chloro-6-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 6-b was repeated except for using methyl 5-chloro-6-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (195.0 mg, 0.61 mmol) to obtain 5-chloro-6-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (160.7 mg, 86%).

¹H-NMR (400 MHz, DMSO-d₆): δ 13.62 (brs, 1H), 9.67 (brs, 1H), 8.20 (s, 1H), 8.14 (s, 1H), 8.03 (s, 1H), 3.12 (s, 3H)

Intermediate 29) Synthesis of 6-bromo-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of 4-bromo-2-fluoro-5-nitrobenzaldehyde

4-Bromo-2-fluorobenzaldehyde (2.0 g, 9.85 mmol) was dissolved in concentrated sulfuric acid (5.2 mL, 98.50 mmol), and 60% HNO₃ (1.0 mL, 12.80 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 4 hours, and extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was recrystallized using i-Pr₂O to obtain 4-bromo-2-fluoro-5-nitrobenzaldehyde (900.0 mg, 37%) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ 10.31 (s, 1H), 8.42 (d, 1H, J=6.4 Hz), 7.67 (d, 1H, J=9.0 Hz).

(b) Synthesis of methyl 6-bromo-5-nitrobenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 26-a was repeated except for using 4-bromo-2-fluoro-5-nitrobenzaldehyde (500 mg, 2.02 mmol) to obtain a yellow compound of methyl 6-bromo-5-nitrobenzo[b]thiophene-2-carboxylate (550.0 mg).

(c) Synthesis of methyl 5-amino-6-bromobenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 13-b was repeated except for using crude methyl 6-bromo-5-nitrobenzo[b]thiophene-2-carboxylate (550.0 mg) to obtain methyl 5-amino-6-bromobenzo[b]thiophene-2-carboxylate (180.0 mg, 2 step yield: 31%).

LC/MS ESI (+): 286 (M+1)

(d) Synthesis of methyl 6-bromo-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 6-a was repeated except for using methyl 5-amino-6-bromobenzo[b]thiophene-2-carboxylate (180.0 mg, 0.63 mmol) to obtain methyl 6-bromo-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (185.7 mg, 81%).

¹H-NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 6.76 (s, 1H), 3.89 (s, 3H), 2.95 (s, 3H).

(e) Synthesis of 6-bromo-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 6-b was repeated except for using methyl 6-bromo-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (185.7 mg, 0.51 mmol) to obtain 6-bromo-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (200.0 mg, 74%).

¹H-NMR (400 MHz, DMSO-d₆): δ 9.52 (s, 1H), 8.48 (s, 1H), 8.05-8.07 (m, 2H), 3.08 (s, 3H)

Intermediate 30) Synthesis of 6-fluoro-5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of methyl 5-[bis(tetrahydrofuran-3-ylsulfonyl)amino]-6-fluoro-benzothiophene-2-carboxylate

Methyl 5-amino-6-fluorobenzo[b]thiophene-2-carboxylate (120.0 mg, 0.53 mmol) was dissolved in CH₂Cl₂ (5.3 mL), and tetrahydrofuran-3-sulfonyl chloride (180.4 mg, 1.06 mmol) and DIPEA (0.2 mL, 1.17 mmol) were added. The reaction mixture was stirred for 15 hours, water was added to quench the reaction. The reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain methyl 5-[bis(tetrahydrofuran-3-ylsulfonyl)amino]-6-fluoro-benzothiophene-2-carboxylate (109.0 mg).

LC/MS ESI (+): 494 (M+1)

(b) Synthesis of 6-fluoro-5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 6-b was repeated except for using crude methyl 5-[bis(tetrahydrofuran-3-ylsulfonyl)amino]-6-fluoro-benzothiophene-2-carboxylate (109.0 mg) to obtain 6-fluoro-5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxylic acid (90.0 mg, 2 step yield: 49%).

LC/MS ESI (+): 346 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 12.07 (s, 1H), 9.97 (s, 1H), 8.13 (s, 1H), 8.06-8.11 (m, 2H), 3.87 (m, 4H), 3.68 (m, 1H), 2.18-2.22 (m, 2H)

Intermediate 31) Synthesis of 6-chloro-5-(2-methoxyethyl)sulfonamido)benzo[b]thiophene-2-carboxylic acid (a) Synthesis of methyl 5-[bis(2-methoxyethylsulfony)amino]-6-chloro-benzothiophene-2-carboxylate

Methyl 5-amino-6-chlorobenzo[b]thiophene-2-carboxylate (400.0 mg, 1.65 mmol) was dissolved in CH₂Cl₂ (6.0 mL), and 2-methoxyethane-1-sulfonyl chloride (0.4 mL, 3.64 mmol) and DIPEA (0.9 mL, 4.95 mmol) were added. The reaction mixture was stirred for 1 hour, water was added to quench the reaction, and then extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain methyl 5-[bis(2-methoxyethylsulfonyl)amino]-6-chloro-benzothiophene-2-carboxylate (350.0 mg, 43%) as an off-white oil.

LC/MS ESI (+): 486 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 8.04 (s, 1H), 8.02 (s, 1H), 4.09-4.16 (m, 2H), 3.97 (s, 3H), 3.89-3.92 (m, 4H), 3.81-3.87 (m, 2H), 3.40 (s, 6H)

(b) Synthesis of 6-chloro-5-((2-methoxyethyl)sulfonamido)benzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 6-b was repeated except for using methyl 5-[bis(2-methoxyethylsulfonyl)amino]-6-chloro-benzothiophene-2-carboxylate (350.0 mg, 0.72 mmol) to obtain 6-chloro-5-(2-methoxyethyl)sulfonamido)benzo[b]thiophene-2-carboxylic acid (220.0 mg, 87%).

LC/MS ESI (+): 350 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 9.64 (s, 1H), 8.33 (s, 1H), 8.07-8.11 (m, 2H), 3.74 (t, 2H, J=6.4 Hz), 3.46 (t, 2H, J=6.4 Hz), 3.24 (s, 3H)

Intermediate 32) Synthesis of (3-methoxy-5-nitrophenyl)(3-(trifluoromethoxy)phenyl)methanone (a) Synthesis of 3-methoxy-5-nitrobenzoic acid

To a mixture of LiOMe (3.6 g, 94.28 mmol) and HMPA (100.0 mL), 3,5-dinitrobenzoic acid (5.0 g, 23.57 mmol) was added at room temperature. The reaction mixture was stirred for 17 hours and heated at 80° C. for 17 hours, and then cooled to room temperature. The reaction mixture was poured into a mixture of 6M H₂SO₄ and ice water, and extracted with Et₂O. The organic extract was washed with 1 N HCl and brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure to obtain 3-methoxy-5-nitrobenzoic acid (4.0 g, 86%) as a yellow solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 13.76 (brs, 1H), 8.21 (m, 1H), 7.95 (t, 1H, J=2.7 Hz), 7.82 (dd, 1H, J=2.7, 1.1 Hz), 3.94 (s, 3H)

(b) Synthesis of 3-methoxy-5-nitrobenzoyl chloride

3-Methoxy-5-nitrobenzoic acid (6.8 g, 34.34 mmol) was dissolved in anhydrous CH₂Cl₂ (10.0 mL), and (COCl)₂ (6.0 mL, 68.68 mmol) and a catalytic amount of anhydrous DMF were added. Stirring was performed at room temperature for 3 hours, and the reaction mixture was concentrated under reduced pressure, followed by adding i-Pr₂O, stirring for 30 minutes and then filtering. The filtrate was concentrated under reduced pressure to obtain 3-methoxy-5-nitrobenzoyl chloride (7.0 g, 95%) as an off-white solid.

(c) Synthesis of (3-methoxy-5-nitrophenyl)(3-(trifluoromethoxy)phenyl)methanone

3-Methoxy-5-nitrobenzoyl chloride (350.0 mg, 1.62 mmol) and (3-(trifluoromethoxy)phenyl)boronic acid (257.0 mg, 1.25 mmol) were dissolved in anhydrous toluene (12.0 mL), and Pd(dppf)₂Cl₂—CH₂Cl₂ (51.0 mg, 0.06 mmol) and K₃PO₄H₂O (575.0 mg, 2.50 mmol) were added. The reaction mixture was heated at 110° C. for 2 hours, and the reaction temperature was cooled to room temperature. Water was added to the reaction mixture, followed by extraction with EtOAc. The organic extract was washed with sat. NaHCO₃ aqueous solution and brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=5:1) to obtain (3-methoxy-5-nitrophenyl)(3-(trifluoromethoxy)phenyl)methanone (232.4 mg, 55%) as an off-white oil.

¹H-NMR (300 MHz, DMSO-d₆): δ 8.00-8.03 (m, 2H), 7.83 (m, 1H), 7.71-7.79 (m, 3H), 7.69 (m, 1H), 3.95 (s, 3H)

Intermediate 33) Synthesis of 3-(difluoromethoxy)-5-nitrobenzoic acid (a) Synthesis of methyl 3-hydroxy-5-nitrobenzoate

To a solution of 3-hydroxy-5-nitrobenzoic acid (3.7 g, 20.00 mmol) in MeOH (70.0 mL), SOCl₂ (12.0 mL) was added at 0° C. The reaction mixture was stirred at 6° C. for 3 hours, and concentrated under reduced pressure. Water was added to the residue, followed by extracting with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure to obtain methyl 3-hydroxy-5-nitrobenzoate (3.9 g) as an off-white solid without purification.

¹H-NMR (300 MHz, DMSO-d₆): δ 10.96 (s, 1H), 8.08 (m, 1H), 7.78 (m, 1H), 7.70 (m, 1H), 3.90 (s, 3H)

(b) Synthesis of methyl 3-(difluoromethoxy)-5-nitrobenzoate

To a solution of crude methyl 3-hydroxy-5-nitrobenzoate (3.9 g) in anhydrous DMF (150.0 mL), sodium 2-chloro-2,2-difluoroacetate (5.0 g, 33.30 mmol) and Na₂CO₃ (1.8 g, 165.00 mmol) were added at room temperature. The reaction mixture was heated at 100° C. for 30 minutes and cooled to room temperature. Water was added to the reaction mixture, followed by extracting with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=5:95 to 30:70) to obtain methyl 3-(difluoromethoxy)-5-nitrobenzoate (2.5 g, 2 step yield: 61%) as a white solid.

¹H-NMR (300 MHz, CDCl₃): δ 8.73 (m, 1H), 8.19 (t, 1H, J=2.1 Hz), 8.13 (s, 1H), 6.65 (t, 1H, J=71.7 Hz), 4.00 (s, 3H)

(c) Synthesis of 3-(difluoromethoxy)-5-nitrobenzoic acid

Methyl-3-(difluoromethoxy)-5-nitrobenzoate (2.5 g, 10.10 mmol) was dissolved in a mixture of THF/H₂O (50.0 mL, 4/1 v/v), and LiOH.H₂O (485.0 mg, 20.20 mmol) was added at 0° C. The reaction mixture was stirred at 5° C. for 12 hours and concentrated under reduced pressure. The residue was acidified to pH 3-4 with 1 N HCl aqueous solution and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure to obtain 3-(difluoromethoxy)-5-nitrobenzoic acid (2.4 g, 100%) as a white solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 14.25 (brs, 1H), 8.47 (s, 1H), 8.22 (s, 1H), 8.06 (s, 1H), 7.53 (t, 1H, J=72.9 Hz)

Intermediate 34) Synthesis of (2-fluorophenyl)(3-nitrophenyl)methanone

To a solution of 1-bromo-2-fluorobenzene (1.0 g, 5.71 mmol) in anhydrous THF (15.0 mL), 1.7 M solution of tert-BuLi in pentane (3.5 mL, 6.00 mmol) was added at −78° C., followed by stirring for 30 minutes. ZnI₂ (1.9 g, 6.00 mmol) was dissolved in anhydrous THF (10.0 mL), and was added to the reaction mixture, followed by stirring at 0° C. for 30 minutes. The reaction mixture was added to a solution of 3-nitrobenzoyl chloride (1.1 g, 5.71 mmol) and Pd₂(dba)₃.CHCl₃ (296.0 mg, 0.29 mmol) in anhydrous THF (15.0 mL) at 0° C., followed by stirring at room temperature for 12 hours. Water was added to the reaction mixture to quench the reaction, followed by extracting with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=5:1) to obtain (2-fluorophenyl)(3-nitrophenyl)methanone (490.0 mg, 35%) as an off-white oil.

¹H-NMR (300 MHz, CDCl₃): δ 8.63 (s, 1H), 8.45 (d, 1H, J=8.0 Hz), 8.17 (d, 1H, J=8.0 Hz), 7.59-7.73 (m, 3H), 7.34 (t, 1H, J=7.6 Hz), 7.20 (t, 1H, J=8.0 Hz)

Intermediate 35) Synthesis of (3-bromo-5-nitrophenyl)(3-methoxyphenyl)methanone

3-Bromo-5-nitrobenzoyl chloride (2.7 g, 10.06 mmol) was dissolved in anhydrous Et₂O (100.0 mL), and (3-methoxyphenyl)boronic acid (1.5 g, 10.06 mmol), Pd(dba)₂ (289.0 mg, 0.50 mmol), PPh₃ (264.0 mg, 1.01 mmol), and copper thiophene-2-carboxylate (1.9 g, 10.06 mmol) were added. The reaction mixture was stirred at room temperature for 12 hours, filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=9:1) to obtain (3-bromo-5-nitrophenyl)(3-methoxyphenyl)methanone (1.2 g, 35%) as an off-white oil.

¹H-NMR (300 MHz, CDCl₃): δ 8.58 (t, 1H, J=1.9 Hz), 8.54 (m, 1H), 8.25 (t, 1H, J=1.9 Hz), 7.44 (t, 1H, J=8.0 Hz), 7.35 (m, 1H), 7.29 (d, 1H, J=7.6 Hz), 7.22 (dd, 1H, J=9.2, 2.7 Hz), 3.88 (s, 3H)

Intermediate 36) Synthesis of (3-bromo-5-nitrophenyl)(4-fluorophenyl)methanone

To a mixture solution of 3-bromo-5-nitrobenzoyl chloride (1.1 g, 4.15 mmol) and fluorobenzene (8.0 mL), AlCl₃ (1.7 g, 12.50 mmol) was added at 0° C. The reaction mixture was heated at 50° C. for 5 hours, cooled to room temperature and poured into ice water, followed by extracting with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=5:1) to obtain (3-bromo-5-nitrophenyl)(4-fluorophenyl)methanone (1.2 g, 86%) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ 8.59 (t, 1H, 1=1.9 Hz), 8.50 (dd, 1H, J=2.3, 1.5 Hz), 8.22 (t, 1H, J=1.5 Hz), 7.85 (dd, 2H, J=8.8, 5.3 Hz), 7.24 (t, 2H, J=8.8 Hz)

Intermediate 37) Synthesis of 1-(dichloro(3-(trifluoromethoxy)phenyl)methyl)-3-methoxy-5-nitrobenzene

(3-Methoxy-5-nitrophenyl)(3-(trifluoromethoxy)phenyl)methanone (264.0 mg, 0.77 mmol) was dissolved in 1,2-dibromoethane (7.0 mL), and PCl₅ (805.9 mg, 3.87 mmol) was added. The reaction mixture was heated at 110° C. for 24 hours and cooled to room temperature. The reaction mixture was poured into NaHCO₃ dissolved in ice water, followed by vigorous stirring. The reaction mixture was extracted with CH₂Cl₂, and the organic extract was dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=5:1) to obtain 1-(dichloro(3-(trifluoromethoxy)phenyl)methyl)-3-methoxy-5-nitrobenzene (243.2 mg, 79%) as an off-white oil.

¹H-NMR (300 MHz, DMSO-d₆): δ 7.94 (t, 1H, J=1.9 Hz), 7.85 (t, 1H, J=1.9 Hz), 7.61-7.68 (m, 3H), 7.55 (brs, 1H), 7.50 (t, 1H, J=1.9 Hz), 3.91 (s, 3H)

Intermediate 38) Synthesis of 1-methoxy-3-nitro-5-(2-(3-(trifluoromethoxy)phenyl)propan-2-yl)benzene

In CH₂Cl₂ (3.0 mL), 1.0 M solution of TiCl₄ in CH₂Cl₂ (123.0 μL, 0.12 mmol) and 1.0 M solution of dimethylzinc in heptane (1.8 mL, 1.84 mmol) were added at −40° C., followed by stirring for 30 minutes. A solution of 1-(dichloro(3-(trifluoromethoxy)phenyl)methyl)-3-methoxy-5-nitrobenzene (243.2 mg, 0.61 mmol) in CH₂Cl₂ (3.0 mL) was slowly added at −40° C. The reaction mixture was stirred at 0° C. for 2 hours, water was added to quench the reaction, and then extracted with CH₂Cl₂. The organic extract was dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=9:1) to obtain 1-methoxy-3-nitro-5-(2-(3-(trifluoromethoxy)phenyl)propan-2-yl)benzene (164.0 mg, 75%) as an off-white oil.

¹H-NMR (300 MHz, DMSO-d₆): δ 7.58-7.60 (m, 2H), 7.45 (m, 1H), 7.29 (dt, 1H, J=8.0, 1.1 Hz), 7.21-7.25 (m, 3H), 3.84 (s, 3H), 1.70 (s, 6H)

Intermediate 39) Synthesis of 3-methoxy-5-(2-(3-(trifluoromethoxy)phenyl)propan-2-yl)aniline

1-Methoxy-3-nitro-5-(2-(3-(trifluoromethoxy)phenyl)propan-2-yl)benzene (164.0 mg, 0.46 mmol) was dissolved in MeOH (4.0 mL). Under an atmosphere of hydrogen gas, Ra—Ni was added, and a reaction was performed at room temperature for 12 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 3-methoxy-5-(2-(3-(trifluoromethoxy)phenyl)propan-2-yl)aniline (121.7 mg, 81%) as an off-white oil.

LC/MS ESI (+): 326 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 7.40 (t, 1H, J=8.0 Hz), 7.23 (d, 1H, J=8.0 Hz), 7.15 (d, 1H, J=8.0 Hz), 7.10 (s, 1H), 5.98-6.00 (m, 2H), 5.92 (t, 1H, J=1.9 Hz), 5.01 (s, 2H), 3.60 (s, 3H), 1.55 (s, 6H)

Intermediate 40) Synthesis of 3-bromo-5-(2-(3-(difluoromethoxy)phenyl)propan-2-yl)aniline

1-Bromo-3-(2-(3-(difluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene (106.6 mg, 0.28 mmol) was dissolved in a mixture of MeOH/H₂O (3.0 mL, 9/1 v/v), and Zn (270.7 mg, 4.14 mmol) and NH₄Cl (73.8 mg, 1.38 mmol) were added at room temperature. The reaction mixture was ultrasonificated at 40° C. for 40 minutes, and then cooled to room temperature, filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=4:1) to obtain 3-bromo-5-(2-(3-(difluoromethoxy)phenyl)propan-2-yl)aniline (91.5 mg, 93%) as an off-white oil.

LC/MS ESI (+): 356 (M+1)

Intermediate 41) Synthesis of 3-(2-(3-bromo-5-nitrophenyl)propan-2-yl)phenol

To a solution of 1-bromo-3-(2-(3-methoxyphenyl)propan-2-yl)-5-nitrobenzene (602.0 mg, 1.72 mmol) in anhydrous CH₂Cl₂ (8.0 mL), 1.0 M solution of BBr₃ in CH₂Cl₂ (8.6 mL, 8.60 mmol) was added at 0° C., followed by stirring at room temperature for 3.5 hours. Water was added at 0° C. to quench the reaction, followed by extraction with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 3-(2-(3-bromo-5-nitrophenyl)propan-2-yl)phenol (570.0 mg, 98%) as an off-white oil.

¹H-NMR (300 MHz, DMSO-d₆): δ 9.31 (s, 1H), 8.22 (t, 1H, J=1.9 Hz), 7.95 (t, 1H, J=1.9 Hz), 7.82 (t, 1H, J=1.9 Hz), 7.11 (t, 1H, J=8.4 Hz), 6.68 (d, 1H, J=8.4 Hz), 6.61-6.63 (m, 2H), 1.65 (s, 6H)

Intermediate 42) Synthesis of 2-(3-(2-(3-bromo-5-nitrophenyl)propan-2-yl)phenoxy)acetamide

3-(2-(3-Bromo-5-nitrophenyl)propan-2-yl)phenol (123.0 mg, 0.37 mmol) was dissolved in anhydrous DMF (3.5 mL), and K₂CO₃ (152.0 mg, 1.10 mmol) and 2-iodoacetamide (135.0 mg, 0.73 mmol) were added. The reaction mixture was stirred at 30° C. for 76 hours, water was added, and then extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:2) to obtain 2-(3-(2-(3-bromo-5-nitrophenyl)propan-2-yl)phenoxy)acetamide (129.1 mg, 83%) as a white solid.

LC/MS ESI (+): 393 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 8.22 (m, 1H), 7.96 (m, 1H), 7.83 (m, 1H), 7.51 (brs, 1H), 7.36 (brs, 1H), 7.25 (td, 1H, J=8.4, 3.1 Hz), 6.78-6.89 (m, 3H), 4.38 (s, 2H), 1.68 (s, 6H)

Intermediate 43) Synthesis of 1-bromo-3-(2-(3-(difluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene

3-(2-(3-Bromo-5-nitrophenyl)propan-2-yl)phenol (122.2 mg, 0.36 mmol) was dissolved in a mixture of CH₃CN/H₂O (3.6 mL, 1/1 v/v), and KOH (407.0 mg, 7.26 mmol) and diethyl (bromodifluoromethyl)phosphonate (129.0 μL, 0.73 mmol) were added. The reaction mixture was heated at 40° C. for 5 hours, and water was added to quench the reaction, followed by extracting with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 1-bromo-3-(2-(3-(difluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene (106.6 mg, 70%) as an off-white oil.

¹H-NMR (300 MHz, DMSO-d₆): δ 8.24 (m, 1H), 7.98 (m, 1H), 7.86 (m, 1H), 7.38 (t, 1H, J=7.6 Hz), 7.25 (t, 1H, J=74.4 Hz), 7.12 (d, 1H, J=7.6 Hz), 7.08 (s, 1H), 7.05 (d, 1H, J=8.0 Hz), 1.71 (s, 6H)

Intermediate 44) Synthesis of 4-(3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-(1,1,2,2-tetrafluoroethoxy)benzyl)-1-methyl-1H-pyrazole

1-(Bromomethyl)-3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-(1,1,2,2-tetrafluoroethoxy)benzene (150.0 mg, 0.24 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (54.5 mg, 0.26 mmol), Pd(PPh₃)₄ (27.5 mg, 0.02 mmol) and Na₂CO₃ (75.4 mg, 0.71 mmol) were added to a mixture of DME/H₂O (4.5 mL, 2/1 v/v) in a sealed tube. The reaction mixture was heated at 100° C. for 4 hours and cooled to room temperature, followed by extracting with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain 4-(3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-(1,1,2,2-tetrafluoro ethoxy)benzyl)-1-methyl-1H-pyrazole (25.9 mg, 22%) as a yellow oil.

LC/MS ESI (+): 486 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.07 (m, 1H), 7.97 (m, 1H), 7.48 (m, 1H), 7.28 (s, 1H), 7.04 (s, 1H), 6.94 (s, 1H), 6.92 (s, 1H), 6.89 (s, 1H), 5.87 (tt, 1H, J=53.1, 2.7 Hz), 3.85 (s, 3H), 3.79 (s, 2H), 1.70 (s, 6H)

Example 1 Synthesis of N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

3-(2-(4-fluorophenyl)propan-2-yl)aniline (36.0 mg, 0.16 mmol), 6-(methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (50.0 mg, 0.17 mmol) and HATU (66.0 mg, 0.17 mmol) were dissolved in anhydrous DMF (1.6 mL), and DIPEA (84.0 μL, 0.48 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours and then extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=95:5) to obtain N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (37.0 mg, 50%) as a white solid.

LC/MS ESI (+): 466 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.68 (s, 1H), 10.08 (s, 1H), 9.60 (s, 1H), 7.73 (d, 1H, J=8.4 Hz), 7.58-7.62 (m, 2H), 7.36 (s, 2H), 7.24-7.30 (m, 3H), 7.10 (t, 2H, J=8.8 Hz), 6.97 (dd, 2H J=8.8, 1.9 Hz), 2.93 (s, 3H), 1.65 (s, 6H)

Through the synthetic method according to Example 1, compounds from Example 2 to Example 106 were synthesized, and the data of each example are as follows.

TABLE 2 Ex. Compound Analysis data 2 6-(methylsulfonamido)-N-(3- LC/MS ESI (+): 448 (M + 1) (2-phenylpropan-2- ¹H-NMR(300 MHz, DMSO-d₆): δ 11.69 (s, 1H), 10.09 yl)phenyl)-1H-indole-2- (s, 1H), 9.60 (s, 1H), 7.73 (d, 1H, J = 8.0 Hz), 7.58~7.64 carboxamide (m, 2H), 7.36 (s, 2H), 7.22~7.32 (m, 5H), 7.16 (t, 1H, J = 6.9 Hz), 6.95~6.99 (m, 2H), 2.93 (s, 3H), 1.66 (s, 6H) 3 N-(3-(2-(4- LC/MS ESI (+): 496 (M + 1) fluorophenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.58 (s, 1H), 10.08 yl)phenyl)-5-methoxy-6- (s, 1H), 8.86 (brs, 1H), 7.72 (d, 1H, J = 8.4 Hz), 7.62 (s, (methylsulfonamido)-1H- 1H), 7.38 (s, 1H), 7.21~7.30 (m, 5H), 7.07~7.13 (m, indole-2-carboxamide 2H), 6.96 (d, 1H, J = 8.0 Hz), 3.85 (s, 3H), 2.90 (s, 3H), 1.65 (s, 6H) 4 N-(3-methoxy-5-(2-(3- LC/MS ESI (+): 562 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.68 (s, 1H), 10.08 pan-2-yl)phenyl)-6- (s, 1H), 9.61 (s, 1H), 7.60 (d, 1H, J = 8.8 Hz), 7.41~7.47 (methylsulfonamido)-1H- (m, 2H), 7.36 (s, 2H), 7.17~7.28 (m, 4H), 6.97 (dd, 1H, indole-2-carboxamide J = 8.8, 1.9 Hz), 6.51 (s, 1H), 3.73 (s, 3H), 2.93 (s, 3H), 1.65 (s, 6H) 5 N-(3-(2-(4- LC/MS ESI (+): 481 (M + 1) fluorophenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.61 (s, 1H), 10.05 yl)phenyl)-6-((N- (s, 1H), 9.55 (s, 1H), 7.72 (d, 1H, J = 8.0 Hz), 7.62 (s, methylsulfamoyl)amino)-1H- 1H), 7.54 (d, 1H, J = 8.8 Hz), 7.33 (s, 2H), 7.24~7.29 (m, indole-2-carboxamide 3H), 7.07~7.13 (m, 3H), 6.95~6.98 (m, 2H), 2.47 (s, 3H), 1.65 (s, 6H) 6 N-(3-(2-(4- LC/MS ESI (+): 451 (M + 1) fluorophenyl)propan-2- ¹H-NMR (300 MHZ, DMSO-d₆): 5 12.39 (s, 1H), 10.35 yl)phenyl)-6- (s, 1H), 8.00 (s, 1H), 7.93 (d, 1H, J = 8.8 Hz), 7.75 (dd, (methylsulfonyl)-1H-indole- 1H, J = 8.8, 1.1 Hz), 7.64 (s, 1H), 7.61 (dd, 1H, J = 9.2, 2-carboxamide 1.5 Hz), 7.58 (s, 1H), 7.25~7.33 (m, 3H), 7.08~7.14 (m, 2H), 7.01 (dd, 1H, J = 8.0, 1.1 Hz), 3.20 (s, 3H), 1.66 (s, 6H) 7 N-(3-(2-(2- LC/MS ESI (+): 466 (M + 1) fluorophenyl)propan-2- ¹H-NMR(300 MHz, DMSO-d₆): δ 11.67 (s, 1H), 10.07 yl)phenyl)-6- (s, 1H), 9.60 (s, 1H), 7.70 (d, 1H, J = 8.8 Hz), 7.52~7.60 (methylsulfonamido)-1H- (m, 3H), 7.36 (s, 2H), 7.21~7.33 (m, 3H), 7.04 (dd, 1H indole-2-carboxamide J = 12.2, 8.0 Hz), 6.96 (d, 1H, J = 8.8 Hz), 6.89 (d, 1H, J = 7.3 Hz), 2.92 (s, 3H), 1.66 (s, 6H) 8 6-(methylsulfonamido)-N-(3-(2- LC/MS ESI (+): 532 (M + 1) (3-(trifluoromethoxy)phenyl)pro- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.68 (s, 1H), 10.10 pan-2-yl)phenyl)-1H-indole- (s, 1H), 9.61 (brs, 1H), 7.76 (d, 1H, J = 7.4 Hz), 7.65 (s, 2-carboxamide 1H), 7.60 (d, 1H, J = 8.8 Hz), 7.43 (t, 1H, J = 7.9 Hz), 7.36 (s, 2H), 7.25~7.32 (m, 2H), 7.15~7.20 (m, 2H), 6.96 (d, 2H, J = 7.9 Hz), 2.93 (s, 3H), 1.67 (s, 6H) 9 N-(3-(2-(3-methoxy-5- LC/MS ESI (+): 562 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.69 (s, 1H), 10.11 pan-2-yl)phenyl)-6- (s, 1H), 9.61 (s, 1H), 7.76 (d, 1H, J = 8.4 Hz), 7.60~7.64 (methylsulfonamido)-1H- (m, 2H), 7.37 (s, 2H), 7.29 (t, 1H, J = 8.0 Hz), 6.97 (d, indole-2-carboxamide 2H, J = 8.4 Hz), 6.79 (d, 2H, J = 6.5 Hz), 6.70 (s, 1H), 3.75 (s, 3H), 2.93 (s, 3H), 1.65 (s, 6H) 10 N-(3-(1-(3-methoxy-5- LC/MS ESI (+): 548 (M + 1) (trifluoromethoxy)phenyl)eth- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.70 (s, 1H), 10.13 yl)phenyl)-6- (s, 1H), 9.62 (s, 1H), 7.60~7.71 (m, 3H), 7.38 (s, 2H), (methylsulfonamido)-1H- 7.30 (t, 1H, J = 7.7 Hz), 7.04 (d, 1H, J = 7.7 Hz), 6.98 (d, indole-2-carboxamide 1H, J = 8.5 Hz), 6.90 (s, 1H), 6.81 (s, 1H), 6.76 (s, 1H), 4.16~4.24 (m, 1H), 3.77 (s, 3H), 2.94 (s, 3H), 1.58 (d, 3H, J = 7.4 Hz) 11 N-(3-(2-(2,4- LC/MS ESI (+): 484 (M + 1) difluorophenyl)propan-2- ¹H-NMR(300 MHz, DMSO-d₆): δ 11.68 (s, 1H), 10.07 yl)phenyl)-6- (s, 1H), 9.60 (s, 1H), 7.70 (d, 1H, J = 8.0 Hz), 7.54~7.61 (methylsulfonamido)-1H- (m, 3H), 7.36 (s, 2H), 7.25 (t, 1H, J = 8.1 Hz), 7.04~7.14 indole-2-carboxamide (m, 2H), 6.97 (dd, 1H J = 8.5, 1.8 Hz), 6.91 (d, 1H, J = 8.1 Hz), 2.93 (s, 3H), 1.65 (s, 6H) 12 N-(3-(2-(3- LC/MS ESI (+): 478 (M + 1) methoxyphenyl)propan-2- ¹H-NMR(300 MHz, DMSO-d₆): δ 11.68 (s, 1H), 10.09 yl)phenyl)-6- (s, 1H), 9.61 (s, 1H), 7.74 (d, 1H, J = 8.1 Hz), 7.58~7.62 (methylsulfonamido)-1H- (m, 2H), 7.37 (s, 2H), 7.27 (t, 1H, J = 7.3 Hz), 7.20 (dd, indole-2-carboxamide 1H J = 8.8, 7.7 Hz), 6.97 (dd, 2H J = 8.8, 1.9 Hz), 6.74~6.81 (m, 3H), 3.70 (s, 3H), 2.93 (s, 3H), 1.64 (s, 6H) 13 N-(3-methoxy-5-(2-(3- LC/MS ESI (+): 592 (M + 1) methoxy-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.68 (s, 1H), 10.08 (trifluoromethoxy)phenyl)pro- (s, 1H), 9.62 (s, 1H), 7.61 (d, 1H, J = 8.8 Hz), 7.47 (s, pan-2-yl)phenyl)-6- 1H), 7.37 (s, 2H), 7.22 (s, 1H), 6.97 (d, 1H, J = 8.8 Hz), (methylsulfonamido)-1H- 6.81 (s, 1H), 6.78 (s, 1H), 6.72 (s, 1H), 6.52 (s, 1H), indole-2-carboxamide 3.76 (s, 3H), 3.73 (s, 3H), 2.93 (s, 3H), 1.63 (s, 6H) 14 N-(3-bromo-5-(2-(4- LC/MS ESI (+): 544 (M + 1) fluorophenyl)propan-2- ¹H-NMR(300 MHz, DMSO-d₆): δ 11.71 (s, 1H), 10.22 yl)phenyl)-6- (s, 1H), 9.64 (s, 1H), 8.04 (s, 1H), 7.58~7.63 (m, 2H), (methylsulfonamido)-1H- 7.37 (s, 2H), 7.28 (dd, 2H J = 8.8, 5.3 Hz), 7.09~7.16 (m, indole-2-carboxamide 3H), 6.98 (dd, 1H J = 8.8, 1.5 Hz), 2.93 (s, 3H), 1.64 (s, 6H) 15 N-(3-bromo-5-(2-(2,4- LC/MS ESI (+): 562 (M + 1) difluorophenyl)propan-2- ¹H-NMR(300 MHz, DMSO-d₆): δ 11.71 (s, 1H), 10.21 yl)phenyl)-6- (s, 1H), 9.64 (s, 1H), 8.04 (s, 1H), 7.53~7.64 (m, 3H), (methylsulfonamido)-1H- 7.36 (s, 2H), 7.10~7.16 (m, 2H), 7.06 (s, 1H), 6.97 (dd, indole-2-carboxamide 1H J = 8.8, 1.9 Hz), 2.93 (s, 3H), 1.64 (s, 6H) 16 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 640 (M + 1) methoxy-5- ¹H-NMR(300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 10.24 (trifluoromethoxy)phenyl)pro- (s, 1H), 9.65 (s, 1H), 8.09 (s, 1H), 7.59~7.64 (m, 2H), pan-2-yl)phenyl)-6- 7.38 (s, 2H), 7.12 (s, 1H), 6.98 (dd, 1H J = 8.8, 1.8 Hz), (methylsulfonamido)-1H- 6.80~6.82 (m, 2H), 6.73 (s, 1H), 3.77 (s, 3H), 2.94 (s, indole-2-carboxamide 3H), 1.64 (s, 6H) 17 N-(3-(difluoromethoxy)-5-(2- LC/MS ESI (+): 532 (M + 1) (4-fluorophenyl)propan-2- ¹H-NMR(300 MHz, DMSO-d₆): δ 11.75 (s, 1H), 10.25 yl)phenyl)-6- (s, 1H), 9.65 (s, 1H), 7.72 (s, 1H), 7.62 (d, 1H, (methylsulfonamido)-1H- J = 8.6 Hz), 7.46 (m, 1H), 7.36~7.38 (m, 2H), 7.28 (dd, indole-2-carboxamide 2H, J = 8.8, 5.5 Hz), 7.23 (t, 1H, J = 74.0 Hz), 7.09~7.17 (m, 2H), 6.98 (dd, 1H, J = 8.4, 1.7 Hz), 6.76 (m, 1H), 2.94 (s, 3H), 1.65 (s, 6H) 18 N-(3-(2-(3-(2-amino-2- LC/MS ESI (+): 599 (M + 1) oxoethoxy)phenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.68 (s, 1H), 10.21 yl)-5-bromophenyl)-6- (s, 1H), 9.60 (s, 1H), 8.06 (s, 1H), 7.60~7.63 (m, 2H), (methylsulfonamido)-1H- 7.51 (s, 1H), 7.38 (s, 1H), 7.37 (s, 1H), 7.34 (s, 1H), indole-2-carboxamide 7.24 (t, 1H, J = 8.0 Hz), 7.08 (s, 1H), 6.99 (dd, 1H, J = 9.2, 1.9 Hz), 6.90 (s, 1H), 6.83 (d, 1H, J = 8.0 Hz), 6.77 (d, 1H, J = 8.4 Hz), 4.38 (s, 2H), 2.94 (s, 3H), 1.64 (s, 6H) 19 N-(3-bromo-5-(2-(4- LC/MS ESI (+): 574 (M + 1) fluorophenyl)propan-2- ¹H-NMR(300 MHz, DMSO-d6): δ 11.58 (s, 1H), 10.19 yl)phenyl)-5-methoxy-6- (s, 1H), 8.77 (s, 1H), 8.04 (s, 1H), 7.61 (s, 1H), 7.41 (s, (methylsulfonamido)-1H- 1H), 7.26~7.31 (m, 3H), 7.23 (s, 1H), 7.09~7.16 (m, indole-2-carboxamide 3H), 3.86 (s, 3H), 2.92 (s, 3H), 1.65 (s, 6H) 20 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 592 (M + 1) (difluoromethoxy)phenyl)pro- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.68 (s, 1H), 10.21 pan-2-yl)phenyl)-6- (s, 1H), 9.61 (s, 1H), 8.07 (s, 1H), 7.60~7.63 (m, 2H), (methylsulfonamido)-1H- 7.34~7.39 (m, 3H), 7.23 (t, 1H, J = 74.4 Hz), 7.08~7.11 indole-2-carboxamide (m, 2H), 6.97~7.05 (m, 3H), 2.94 (s, 3H), 1.65 (s, 6H) 21 N-(3-chloro-5-(2-(4- LC/MS ESI (+): 500 (M + 1) fluorophenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.68 (s, 1H), 10.21 yl)phenyl)-6- (s, 1H), 9.59 (s, 1H), 7.92~7.93 (m, 1H), 7.60 (d, 1H, (methylsulfonamido)-1H- J = 8.4 Hz), 7.54 (s, 1H), 7.36~7.38 (m, 2H), 7.26~7.30 indole-2-carboxamide (m, 2H), 7.09~7.15 (m, 2H), 6.96~7.00 (m, 2H), 2.93 (s, 3H), 1.64 (s, 6H) 22 N-(3-bromo-5-(2-(3-ethoxy-5- LC/MS ESI (+): 654 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 10.25 pan-2-yl)phenyl)-6- (s, 1H), 9.64 (s, 1H), 8.09 (s, 1H), 7.57~7.65 (m, 2H), (methylsulfonamido)-1H- 7.37 (s, 2H), 7.12 (s, 1H), 6.98 (dd, 1H, J = 8.4, 1.7 Hz), indole-2-carboxamide 6.75~6.80 (m, 2H), 6.73 (s, 1H), 4.02 (q, 2H, J = 7.0 Hz), 2.94 (s, 3H), 1.64 (s, 6H), 1.30 (t, 3H, J = 7.0 Hz) 23 N-(3-bromo-5-(2-(2-fluoro-5- LC/MS ESI (+): 628 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.67 (s, 1H), 10.20 pan-2-yl)phenyl)-6- (s, 1H), 9.59 (s, 1H), 8.04 (m, 1H), 7.61 (d, 1H, (methylsulfonamido)-1H- J = 8.4 Hz), 7.56 (m, 1H), 7.49 (m, 1H), 7.35~7.38 (m, indole-2-carboxamide 3H), 7.24 (dd, 1H, J = 11.1, 8.8 Hz), 7.06 (m, 1H), 6.99 (dd, 1H, J = 8.8, 1.9 Hz), 2.94 (s, 3H), 1.66 (s, 6H) 24 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 596 (M + 1) methoxy-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 11.73 (s, 1H), 10.26 (trifluoromethoxy)phenyl)pro- (s, 1H), 9.65 (s, 1H), 7.96 (s, 1H), 7.63 (d, 1H, pan-2-yl)phenyl)-6- J = 8.8 Hz), 7.55 (s, 1H), 7.38 (s, 2H), 7.00 (s, 1H), 6.99 (methylsulfonamido)-1H- (d, 1H, J = 8.8 Hz), 6.81 (s, 2H), 6.73 (s, 1H), 3.77 (s, indole-2-carboxamide 3H), 2.94 (s, 3H), 1.65 (s, 6H) 25 N-(3-(2-(4- LC/MS ESI (+): 457 (M + 1) fluorophenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.01 (s, 1H), 10.25 yl)phenyl)-5- (s, 1H), 7.74 (d, 1H, J = 8.4 Hz), 7.70 (s, 1H), 7.62 (s, (trifluoromethoxy)-1H- 1H), 7.52 (d, 1H, J = 8.8 Hz), 7.46 (s, 1H), 7.24~7.31 (m, indole-2-carboxamide 3H), 7.20 (dd, 1H, J = 9.2, 1.5 Hz), 7.07~7.13 (m, 2H), 6.99 (d, 1H, J = 8.4 Hz), 1.65 (s, 6H) 26 N-(3-(2-(4- LC/MS ESI (+): 483 (M + 1) fluorophenyl)propan-2- ¹H-NMR(300 MHz, DMSO-d₆): δ 10.39 (brs, 1H), 9.92 yl)phenyl)-5- (m, 1H), 8.29 (s, 1H), 8.01 (d, 1H, J = 8.8 Hz), 7.98 (m, (methylsulfonamido)ben- 1H), 7.70 (m, 1H), 7.61 (m, 1H), 7.25~7.37 (m, 4H), zo[b]thiophene-2-carboxamide 7.08~7.16 (m, 2H), 7.01 (d, 1H, J = 8.8 Hz), 3.01 (s, 3H), 1.66 (s, 6H) 27 N-(3-(2-(2,4- LC/MS ESI (+): 501 (M + 1) difluorophenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.37 (s, 1H), 9.86 (s, yl)phenyl)-5- 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.8 Hz), 7.78 (d, 1H, (methylsulfonamido)ben- J = 1.9 Hz), 7.68 (dd, 1H, J = 7.6, 1.5 Hz), 7.56~7.63 (m, zo[b]thiophene-2-carboxamide 1H), 7.53~7.54 (m, 1H), 7.35 (dd, 1H, J = 8.8, 2.2 Hz), 7.27 (t, 1H, J = 8.0 Hz), 7.05~7.15 (m, 2H), 6.93 (d, 1H, J = 8.8 Hz), 3.01 (s, 3H), 1.65 (s, 6H) 28 N-(3-(2-(4- LC/MS ESI (+): 467 (M + 1) fluorophenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.44 (s, 1H), 9.74 yl)phenyl)-5- (brs, 1H), 7.62~7.75 (m, 5H), 7.23~7.36 (m, 4H), (methylsulfonamido)benzo- 7.07~7.13 (m, 2H), 7.00 (d, 1H, J = 8.0 Hz), 2.97(s, 3H), furan-2-carboxamide 1.64(s, 6H) 29 N-(3-(2-(2,4- LC/MS ESI (+): 485 (M + 1) difluorophenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.44 (s, 1H), 9.74 (s, yl)phenyl)-5- 1H), 7.54~7.74 (m, 6H), 7.34 (dd, 1H, J = 8.8, 2.3 Hz), (methylsulfonamido)benzo- 7.26 (t, 1H, J = 8.0 Hz), 7.04~7.11 (m, 2H), 6.93 (d, 1H, furan-2-carboxamide J = 8.4 Hz), 2.97 (s, 3H), 1.64 (s, 6H) 30 N-(3-(2-(4- LC/MS ESI (+): 483 (M + 1) fluorophenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.38 (s, 1H), 10.07 yl)phenyl)-6- (s, 1H), 8.27 (s, 1H), 7.94 (d, 1H, J = 8.8 Hz), 7.81 (d, 1H, (methylsulfonamido)ben- J = 1.5 Hz), 7.68 (d, 1H, J = 8.0 Hz), 7.59~7.60 (m, 1H), zo[b]thiophene-2-carboxamide 7.22~7.32 (m, 4H), 7.07~7.14 (m, 2H), 6.99 (d, 1H, J = 8.0 Hz), 3.07 (s, 3H), 1.64 (s, 6H) 31 N-(3-(2-(2- LC/MS ESI (+): 483 (M + 1) fluorophenyl)propan-2- ¹H-NMR(300 MHz, DMSO-d₆): δ 10.38 (s, 1H), 9.87 (s, yl)phenyl)-5- 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.8 Hz), 7.78 (d, 1H, (methylsulfonamido)ben- J = 1.9 Hz), 7.66 (d, 1H, J = 8.4 Hz), 7.52~7.58 (m, 2H), zo[b]thiophene-2-carboxamide 7.21~7.36 (m, 4H), 7.02 (dd, 1H, J = 12.2, 8.4 Hz), 6.93 (d, 1H, J = 8.0 Hz), 3.01 (s, 3H), 1.66 (s, 6H) 32 N-(3-bromo-5-(2-(4- LC/MS ESI (+): 561 (M + 1) fluorophenyl)propan-2- ¹H-NMR(300 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.88 (s, yl)phenyl)-5- 1H), 8.28 (s, 1H), 8.00~8.03 (m, 2H), 7.79 (d, 1H, (methylsulfonamido)ben- J = 2.3 Hz), 7.55 (t, 1H, J = 1.9 Hz), 7.35 (dd, 1H, J = 8.8, zo[b]thiophene-2-carboxamide 2.3 Hz), 7.25~7.30 (m, 2H), 7.10~7.16 (m, 3H), 3.01 (s, 3H), 1.66 (s, 6H) 33 N-(3-(2-(3-methoxy-5- LC/MS ESI (+): 579 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.33 (s, 1H), 9.77 (s, pan-2-yl)phenyl)-5- 1H), 8.27 (s, 1H), 8.00 (d, 1H, J = 8.8 Hz), 7.79 (d, 1H, (methylsulfonamido)ben- J = 1.9 Hz), 7.70 (d, 1H, J = 7.9 Hz), 7.63 (s, 1H), 7.36 (dd, zo[b]thiophene-2-carboxamide 1H, J = 8.8, 2.3 Hz), 7.31 (t, 1H, J = 7.9 Hz), 7.10 (d, 1H, J = 7.9 Hz), 6.80 (s, 1H), 6.76 (s, 1H), 6.70 (s, 1H), 3.76 (s, 3H), 3.00 (s, 3H), 1.66 (s, 6H) 34 N-(3-methoxy-5-(2-(3- LC/MS ESI (+): 609 (M + 1) methoxy-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.31 (s, 1H), 9.78 (s, (trifluoromethoxy)phenyl)pro- 1H), 8.27 (s, 1H), 7.99 (d, 1H, J = 8.8 Hz), 7.78 (d, 1H, pan-2-yl)phenyl)-5- J = 1.9 Hz), 7.42 (s, 1H), 7.36 (dd, 1H, J = 8.8, 2.3 Hz), (methylsulfonamido)ben- 7.21 (s, 1H), 6.81 (s, 1H), 6.76 (s, 1H), 6.71 (s, 1H), zo[b]thiophene-2-carboxamide 6.56 (s, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.00 (s, 3H), 1.64 (s, 6H) 35 N-(3-bromo-5-(2-(2,4- LC/MS ESI (+): 579 (M + 1) difluorophenyl)propan-2- ¹H-NMR(300 MHz, DMSO-d₆): δ 10.51 (s, 1H), 9.88 (s, yl)phenyl)-5- 1H), 8.27 (s, 1H), 8.00~8.03 (m, 2H), 7.78 (d, 1H, (methylsulfonamido)ben- J = 2.2 Hz), 7.57~7.65 (m, 1H), 7.48 (s, 1H), 7.35 (dd, 1H, zo[b]thiophene-2-carboxamide J = 8.5, 2.2 Hz), 7.09~7.17 (m, 3H), 3.01 (s, 3H), 1.64 (s, 6H) 36 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 657 (M + 1) methoxy-5- ¹H-NMR(300 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.88 (s, (trifluoromethoxy)phenyl)pro- 1H), 8.28 (s, 1H), 8.00~8.03 (m, 2H), 7.79 (d, 1H, pan-2-yl)phenyl)-5- J = 2.2 Hz), 7.57 (s, 1H), 7.35 (dd, 1H, J = 8.8, 2.2 Hz), 7.16 (methylsulfonamido)ben- (s, 1H), 6.81 (s, 2H), 6.72 (s, 1H), 3.77 (s, 3H), 3.01 (s, zo[b]thiophene-2-carboxamide 3H), 1.64 (s, 6H) 37 5-(methylsulfonamido)-N-(3-(2- LC/MS ESI (+): 549 (M + 1) (3-(trifluoromethoxy)phenyl)pro- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.41 (s, 1H), 9.88 (s, pan-2-yl)phenyl)benzo[b]thio- 1H), 8.28 (s, 1H), 8.00 (d, 1H, J = 8.5 Hz), 7.78 (d, 1H, phene-2-carboxamide J = 1.8 Hz), 7.71 (d, 1H, J = 8.1 Hz), 7.63 (s, 1H), 7.44 (t, 1H, J = 8.1 Hz), 7.34 (dd, 1H, J = 8.8, 2.2 Hz), 7.31 (t, 1H, J = 8.1 Hz), 7.25 (d, 1H, J = 7.7 Hz), 7.19 (d, 1H, J = 8.1 Hz), 7.15 (s, 1H), 7.00 (d, 1H, J = 7.7 Hz), 3.00 (s, 3H), 1.67 (s, 6H) 38 N-(3-(2-(3- LC/MS ESI (+): 495 (M + 1) methoxyphenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.39 (s, 1H), 9.87 (s, yl)phenyl)-5- 1H), 8.29 (s, 1H), 8.00 (d, 1H, J = 8.5 Hz), 7.77 (d, 1H, (methylsulfonamido)ben- J = 2.2 Hz), 7.69 (d, 1H, J = 8.1 Hz), 7.60 (s, 1H), 7.34 (dd, zo[b]thiophene-2-carboxamide 1H, J = 8.8, 2.2 Hz), 7.28 (t, 1H, J = 8.1 Hz), 7.21 (t, 1H, J = 7.7 Hz), 7.00 (d, 1H, J = 8.5 Hz), 6.75~6.80 (m, 3H), 3.70 (s, 3H), 3.00 (s, 3H), 1.64 (s, 6H) 39 N-(3-(difluoromethoxy)-5-(2- LC/MS ESI (+): 549 (M + 1) (4-fluorophenyl)propan-2- ¹H-NMR(300 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.89 (s, yl)phenyl)-5- 1H), 8.29 (s, 1H), 8.02 (d, 1H, J = 8.6 Hz), 7.79 (d, 1H, (methylsulfonamido)ben- J = 2.1 Hz), 7.66 (m, 1H), 7.43 (s, 1H), 7.36 (dd, 1H, zo[b]thiophene-2-carboxamide J = 8.6, 2.1 Hz), 7.28 (dd, 2H, J = 8.8, 5.5 Hz), 7.23 (t, 1H, J = 74.0 Hz), 7.13 (t, 2H, J = 8.9 Hz), 6.80 (m, 1H), 3.02 (s, 3H), 1.65 (s, 6H) 40 N-(3-chloro-5-(2-(4- LC/MS ESI (+): 517 (M + 1) fluorophenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.52 (s, 1H), 9.84 (s, yl)phenyl)-5- 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.87 (t, 1H, (methylsulfonamido)ben- J = 1.5 Hz), 7.79 (d, 1H, J = 1.9 Hz), 7.51 (s, 1H), 7.36 (dd, zo[b]thiophene-2-carboxamide 1H, J = 8.8, 1.9 Hz), 7.26~7.31 (m, 2H), 7.10~7.16 (m, 2H), 7.00 (t, 1H, J = 1.9 Hz), 3.01 (s, 3H), 1.65 (s, 6H) 41 N-(difluoromethoxy)-5-(2- LC/MS ESI (+): 645 (M + 1) (3-methoxy-5- ¹H-NMR(300 MHz, DMSO-d₆): δ 10.50 (s, 1H), 9.84 (s, (trifluoromethoxy)phenyl)pro- 1H), 8.29 (s, 1H), 8.02 (d, 1H, J = 8.5 Hz), 7.79 (s, 1H), pan-2-yl)phenyl)-5- 7.68 (s, 1H), 7.47 (s, 1H), 7.36 (d, 1H, J = 8.6 Hz), 7.22 (t, (methylsulfonamido)ben- 1H, J = 74.0 Hz), 6.70~6.83 (m, 4H), 3.77 (s, 3H), 3.01 zo[b]thiophene-2-carboxamide (s, 3H), 1.65 (s, 6H) 42 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 613 (M + 1) methoxy-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.51 (s, 1H), 9.82 (s, (trifluoromethoxy)phenyl)pro- 1H), 8.23 (s, 1H), 7.96 (d, 1H, J = 8.8 Hz), 7.84 (s, 1H), pan-2-yl)phenyl)-5- 7.74 (d, 1H, J = 1.6 Hz), 7.46 (s, 1H), 7.30 (dd, 1H, J = 8.8, (methylsulfonamido)ben- 2.2 Hz), 6.98 (s, 1H), 6.74 (s, 2H), 6.67 (s, 1H), 3.71 (s, zo[b]thiophene-2-carboxamide 3H), 2.96 (s, 3H), 1.58 (s, 6H) 43 N-(3-(2-(3-(2-amino-2- LC/MS ESI (+): 616 (M + 1) oxoethoxy)phenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.51 (s, 1H), 9.84 (s, yl)-5-bromophenyl)-5- 1H), 8.28 (s, 1H), 8.01~8.03 (m, 2H), 7.79 (s, 1H), 7.58 (methylsulfonamido)ben- (s, 1H), 7.52 (s, 1H), 7.33~7.38 (m, 2H) 7.24 (t, 1H, zo[b]thiophene-2-carboxamide J = 8.0 Hz), 7.13 (s, 1H), 6.89 (s, 1H), 6.76~6.84 (m, 2H), 4.38 (s, 2H), 3.01 (s, 3H), 1.64 (s, 6H) 44 N-(3-(2-(5-(2-amino-2- LC/MS ESI (+): 634 (M + 1) oxoethoxy)-2- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.88 fluorophenyl)propan-2-yl)-5- (brs, 1H), 8.28 (s, 1H), 8.01~8.03 (m, 2H), 7.79 (m, 1H), bromophenyl)-5- 7.64 (s, 1H), 7.52 (s, 1H), 7.45 (s, 1H), 7.36 (m, 1H), (methylsulfonamido)ben- 7.18 (m, 1H), 7.08 (s, 1H), 7.02 (dd, 1H, J = 11.3, 9.0 Hz), zo[b]thiophene-2-carboxamide 6.86 (m, 1H), 4.45 (s, 2H), 3.01 (s, 3H), 1.63 (s, 6H) 45 N-(3-(2-(3-((1-amino-2- LC/MS ESI (+): 644 (M + 1) methyl-1-oxopropan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.89 (s, yl)oxy)phenyl)propan-2-yl)- 1H), 8.29 (s, 1H), 7.99~8.03 (m, 2H), 7.78 (d, 1H, 5-bromophenyl)-5- J = 1.9 Hz), 7.61 (m, 1H), 7.52 (s, 1H), 7.35 (dd, 1H, (methylsulfonamido)ben- J = 8.8, 1.9 Hz), 7.25 (s, 1H), 7.21 (t, 1H, J = 8.0 Hz), 7.10 zo[b]thiophene-2-carboxamide (m, 1H), 6.87 (m, 1H), 6.78 (m, 1H), 6.70 (m, 1H), 3.01 (s, 3H), 1.62 (s, 6H), 1.38 (s, 6H) 46 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 609 (M + 1) (difluoromethoxy)phenyl)pro- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.52 (s, 1H), 9.85 (s, pan-2-yl)phenyl)-5- 1H), 8.28 (s, 1H), 8.00~8.03 (m, 2H), 7.79 (d, 1H, (methylsulfonamido)ben- J = 1.9 Hz), 7.59 (s, 1H), 7.34~7.39 (m, 2H) 7.24 (t, 1H, zo[b]thiophene-2-carboxamide J = 74.0 Hz), 7.15 (s, 1H), 7.09 (d, 1H, J = 8.0 Hz), 7.01~7.04 (m, 2H), 3.01 (s, 3H), 1.65 (s, 6H) 47 N-(3-bromo-5-(2-(2-fluoro-5- LC/MS ESI (+): 645 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.88 (s, pan-2-yl)phenyl)-5- 1H), 8.27 (s, 1H), 8.01~8.03 (m, 2H), 7.79 (m, 1H), 7.51 (methylsulfonamido)ben- (s, 2H), 7.34~7.41 (m, 2H), 7.25 (dd, 1H, J = 11.1, zo[b]thiophene-2-carboxamide 9.3 Hz), 7.10 (s, 1H), 3.01 (s, 3H), 1.66 (s, 6H) 48 N-(3-bromo-5-(2-(3-ethoxy- LC/MS ESI (+): 671 (M + 1) 5-(trifluoromethoxy)phenyl)pro- ¹H-NMR(300 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.88 pan-2-yl)phenyl)-5- (brs, 1H), 8.28 (s, 1H), 8.00~8.06 (m, 2H), 7.79 (d, 1H, (methylsulfonamido)ben- J = 2.0 Hz), 7.57 (s, 1H), 7.35 (dd, 1H, J = 8.8, 2.1 Hz), 7.16 zo[b]thiophene-2-carboxamide (s, 1H), 6.75~6.80 (m, 2H), 6.72 (s, 1H), 4.02 (q, 2H, J = 7.0 Hz), 3.01 (s, 3H), 1.63 (s, 6H), 1.30 (t, 3H, J = 6.9 Hz) 49 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 685 (M + 1) isopropoxy-5- ¹H-NMR(300 MHz, DMSO-d₆): δ 10.56 (s, 1H), 9.86 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.29 (s, 1H), 8.00~8.07 (m, 2H), 7.79 (d, 1H, pan-2-yl)phenyl)-5- J = 2.1 Hz), 7.58 (s, 1H), 7.36 (dd, 1H, J = 8.7, 2.1 Hz), 7.17 (methylsulfonamido)ben- (s, 1H), 6.78 (s, 1H), 6.69~6.74 (m, 2H), 4.63 (m, 1H), zo[b]thiophene-2-carboxamide 3.01 (s, 3H), 1.63 (s, 6H), 1.23 (d, 6H, J = 6.0 Hz) 50 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 642 (M + 1) (morpholinomethyl)phenyl)pro- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.89 (s, pan-2-yl)phenyl)-5- 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.98 (s, 1H), (methylsulfonamido)ben- 7.79 (d, 1H, J = 1.8 Hz), 7.59 (s, 1H), 7.36 (dd, 1H, J = 8.8, zo[b]thiophene-2-carboxamide 2.0 Hz), 7.28 (t, 1H, J = 7.7 Hz), 7.18 (d, 1H, J = 7.7 Hz), 7.09~7.12 (m, 3H), 3.51 (s, 4H), 3.42 (s, 2H), 3.01 (s, 3H), 2.29 (s, 4H), 1.64 (s, 6H) 51 N-(3-(2-(4- LC/MS ESI (+): 497 (M + 1) fluorophenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.26 (s, 1H), 9.87 (s, yl)phenyl)-3-methyl-6- 1H), 8.00 (d, 1H, J = 8.4 Hz), 7.68 (d, 1H, J = 1.9 Hz), (methylsulfonamido)ben- 7.57~7.60 (m, 2H), 7.37 (dd, 1H, J = 8.8, 1.9 Hz), zo[b]thiophene-2-carboxamide 7.23~7.30 (m, 3H), 7.07~7.13 (m, 2H), 6.97 (d, 1H, J = 8.0 Hz), 3.01 (s, 3H), 2.54 (s, 3H), 1.63 (s, 6H) 52 N-(3-(2-(4- LC/MS ESI (+): 497 (M + 1) fluorophenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.25 (s, 1H), 9.86 (s, yl)phenyl)-3-methyl-5- 1H), 7.99 (d, 1H, J = 8.4 Hz), 7.68 (d, 1H, J = 1.9 Hz), (methylsulfonamido)ben- 7.57~7.60 (m, 2H), 7.37 (dd, 1H, J = 8.4, 2.2 Hz), zo[b]thiophene-2-carboxamide 7.23~7.30 (m, 3H), 7.07~7.13 (m, 2H), 6.97 (d, 1H, J = 7.6 Hz), 3.01 (s, 3H), 2.54 (s, 3H), 1.63 (s, 6H) 53 N-(3-bromo-5-(3-(4- LC/MS ESI (+): 589 (M + 1) fluorophenyl)pentan-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.47 (s, 1H), 9.83 (s, yl)phenyl)-5- 1H), 8.27 (s, 1H), 7.98~8.02 (m, 2H), 7.78 (d, 1H, (methylsulfonamido)ben- J = 2.0 Hz), 7.53 (s, 1H), 7.35 (dd, 1H, J = 8.7, 2.1 Hz), zo[b]thiophene-2-carboxamide 7.19~7.23 (m, 2H), 7.09~7.15 (m, 2H), 7.05 (s, 1H), 3.00 (s, 3H), 2.08 (q, 4H, J = 7.5 Hz), 0.59 (t, 6H, J = 7.2 Hz) 54 N-(3-methoxy-5-(3-(3- LC/MS ESI (+): 637 (M + 1) methoxy-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.33 (s, 1H), 9.80 (trifluoromethoxy)phenyl)pen- (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.8 Hz), 7.79 (d, tan-3-yl)phenyl)-5- 1H, J = 1.9 Hz), 7.42 (s, 1H), 7.35 (dd, 1H, J = 8.8, 2.3 Hz), (methylsulfonamido)ben- 7.15 (s, 1H), 6.77 (s, 1H), 6.75 (s, 1H), 6.66 (s, 1H), zo[b]thiophene-2-carboxamide 6.50 (s, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 3.01 (s, 3H), 2.05 (q, 4H, J = 7.3 Hz), 0.60 (t, 6H, J = 7.3 Hz) 55 N-(3-methoxy-5-(3-(3- LC/MS ESI (+): 620 (M + 1) methoxy-5- ¹H-NMR(300 MHz, DMSO-d₆): δ 11.65 (s, 1H), 10.04 (trifluoromethoxy)phenyl)pen- (s, 1H), 9.59 (brs, 1H), 7.60 (d, 1H, J = 8.8 Hz), 7.48 (s, tan-3-yl)phenyl)-6- 1H), 7.38 (d, 1H, J = 1.9 Hz), 7.35 (d, 1H, J = 1.9 Hz), 7.18 (methylsulfonamido)-1H- (s, 1H), 6.98 (dd, 1H, J = 8.4, 1.9 Hz), 6.76 (s, 2H), 6.66 indole-2-carboxamide (s, 1H), 6.47 (s, 1H), 3.75 (s, 3H), 3.73 (s, 3H), 2.93 (s, 3H), 2.07 (q, 4H, J = 7.3 Hz), 0.61 (t, 6H, J = 7.3 Hz) 56 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 658 (M + 1) methoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.66 (s, 1H), 10.17 (trifluoromethoxy)phenyl)pro- (s, 1H), 8.53 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 8.03 (s, pan-2-yl)phenyl)-5- 1H), 7.58 (s, 1H), 7.19 (s, 1H), 6.82 (s, 2H), 6.74 (s, (methylsulfonamido)thieno[2,3- 1H), 3.78 (s, 3H), 3.08 (s, 3H), 1.65 (s, 6H) b]pyridine-2-carboxamide 57 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 614 (M + 1) methoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.68 (s, 1H), 10.14 (trifluoromethoxy)phenyl)pro- (s, 1H), 8.54 (s, 1H), 8.29 (s, 1H), 8.21 (s, 1H), 7.90 (s, pan-2-yl)phenyl)-5- 1H), 7.53 (s, 1H), 7.07 (s, 1H), 6.82 (s, 2H), 6.74 (s, (methylsulfonamido)thieno[2,3- 1H), 3.78 (s, 3H), 3.09 (s, 3H), 1.66 (s, 6H) b]pyridine-2-carboxamide 58 N-(3-chloro-5-(2-(3-ethoxy-5- LC/MS ESI (+): 627 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.87 pan-2-yl)phenyl)-5- (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.6 Hz), 7.90 (s, (methylsulfonamido)ben- 1H), 7.79 (s, 1H), 7.52 (s, 1H), 7.35 (d, 1H, J = 8.6 Hz), zo[b]thiophene-2-carboxamide 7.04 (s, 1H), 6.72~6.78 (m, 3H), 4.01 (q, 2H, J = 6.8 Hz), 3.01 (s, 3H), 1.64 (s, 6H), 1.30 (t, 3H, J = 6.8 Hz) 59 N-(3-chloro-5-(2-(3-ethoxy-5- LC/MS ESI (+): 610 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR (400 MHz, DMSO-d₆): δ 11.72 (s, 1H), 10.25 pan-2-yl)phenyl)-6- (s, 1H), 9.64 (s, 1H), 7.96 (s, 1H), 7.62 (d, 1H, (methylsulfonamido)-1H- J = 8.6 Hz), 7.55 (s, 1H), 7.37~7.39 (m, 2H), 6.97~7.00 indole-2-carboxamide (m, 2H), 6.73~6.78 (m, 3H), 4.03 (q, 2H, J = 6.8 Hz), 2.94 (s, 3H), 1.64 (s, 6H), 1.30 (t, 3H, J = 6.8 Hz) 60 N-(3-bromo-5-(2-(3-ethoxy-5- LC/MS ESI (+): 672 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 10.55 pan-2-yl)phenyl)-5- (s, 1H), 8.44 (d, 1H, J = 8.9 Hz), 8.40 (s, 1H), 8.05 (m, (methylsulfonamido)thieno[3,2- 1H), 7.60 (m, 1H), 7.17 (m, 1H), 7.04 (d, 1H, J = 8.8 Hz), b]pyridine-2-carboxamide 6.77 (s, 2H), 6.72 (s, 1H), 4.02 (q, 2H, J = 7.0 Hz), 3.42 (s, 3H), 1.64 (s, 6H), 1.30 (t, 3H, J = 7.0 Hz) 61 N-(3-bromo-5-(2-(3-ethoxy-5- LC/MS ESI (+): 672 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.70 (s, 1H), 10.54 pan-2-yl)phenyl)-5- (brs, 1H), 9.09 (s, 1H), 8.26 (s, 1H), 8.03 (m, 1H), 7.55 (methylsulfonamido)thieno[2,3- (s, 1H), 7.51 (s, 1H), 7.20 (m, 1H), 6.78 (s, 2H), 6.72 (s, c]pyridine-2-carboxamide 1H), 4.02 (q, 2H, J = 7.2 Hz), 3.30 (s, 3H), 1.64 (s, 6H), 1.30 (t, 3H, J = 6.8 Hz) 62 N-(3-chloro-5-(2-(2-fluoro-5- LC/MS ESI (+): 601 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.86 pan-2-yl)phenyl)-5- (brs, 1H), 8.26 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.87 (m, (methylsulfonamido)ben- 1H), 7.79 (d, 1H, J = 1.9 Hz), 7.49~7.52 (m, 1H), 7.47 (s, zo[b]thiophene-2-carboxamide 1H), 7.34~7.39 (m, 2H), 7.25 (dd, 1H, J = 11.1, 9.0 Hz), 6.97 (m, 1H), 3.00 (s, 3H), 1.66 (s, 6H) 63 N-(3-fluoro-5-(2-(3- LC/MS ESI (+): 597 (M + 1) methoxy-5- ¹H-NMR(400 MHz, DMSO-d₆); 10.56 (s, 1H), (trifluoromethoxy)phenyl)pro- 9.86 (s, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.79 (s, pan-2-yl)phenyl)-5- 1H), 7.68 (d, 1H, J = 11.0 Hz), 7.35~7.38 (m, 2H), (methylsulfonamido)ben- 6.79~6.86 (m, 3H), 6.72 (s, 1H), 3.76 (s, 3H), 3.01 (s, zo[b]thiophene-2-carboxamide 3H), 1.65 (s, 6H) 64 N-(3-chloro-5-(2- LC/MS ESI (+): 499 (M + 1) phenylpropan-2-yl)phenyl)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.86 (methylsulfonamido)ben- (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.87 (s, zo[b]thiophene-2-carboxamide 1H), 7.79 (s, 1H), 7.54 (s, 1H), 7.20~7.37 (m, 6H), 7.00 (s, 1H), 3.01 (s, 3H), 1.65 (s, 6H) 65 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 517 (M + 1) fluorophenyl)propan-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 9.90 (s, yl)phenyl)-5- 1H), 8.29 (s, 1H), 8.03 (d, 1H, J = 8.8 Hz), 7.90 (t, 1H, (methylsulfonamido)ben- J = 2.0 Hz), 7.80 (d, 1H, J = 2.0 Hz), 7.52 (t, 1H, J = 1.6 Hz), zo[b]thiophene-2-carboxamide 7.34~7.40 (m, 2H), 7.07~7.11 (m, 2H), 7.05~7.06 (m, 2H), 3.02 (s, 3H), 1.67 (s, 6H) 66 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 726 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.74 (brs, 1H), 8.82 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.50 (s, 1H), 7.84 (m, 2H), 7.55 (d, 1H, pan-2-yl)phenyl)-5- J = 8.8 Hz), 7.52 (s, 1H), 7.06 (s, 1H), 6.77 (s, 1H), 6.74 (methylsulfonamido)-4- (m, 1H), 6.72 (s, 1H), 4.60~4.66 (m, 1H), 3.84 (m, 4H), morpholinobenzo[b]thio- 3.22~3.26 (brs, 3H), 3.02~3.05 (m, 4H), 1.66 (s, 6H), phene-2-carboxamide 1.24 (d, 6H, J = 6.0 Hz) 67 N-(3-chloro-5-(2-(3-fluoro-5- LC/MS ESI (+): 547 (M + 1) methoxyphenyl)propan-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.86 yl)phenyl)-5- (brs, 1H), 8.27 (s, 1H), 8.00 (d, 1H, J = 8.7 Hz), 7.87 (s, (methylsulfonamido)ben- 1H), 7.77 (d, 1H, J = 2.0 Hz), 7.48 (s, 1H), 7.33 (dd, 1H, zo[b]thiophene-2-carboxamide J = 8.7, 2.0 Hz), 7.03 (s, 1H), 6.60~6.70 (m, 1H), 6.58~6.61 (m, 2H), 3.72 (s, 3H), 2.99 (s, 3H), 1.61 (s, 6H) 68 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 641 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 9.89 (s, (trifluoromethoxy)phenyl)pro- 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.0 Hz), 7.91 (s, 1H), pan-2-yl)phenyl)-5- 7.79 (s, 1H), 7.54 (s, 1H), 7.36 (d, 1H, J = 8.0 Hz), 7.06 (s, (methylsulfonamido)ben- 1H), 6.78 (s, 1H), 6.74 (s, 1H), 6.72 (s, 1H), 4.59~4.68 zo[b]thiophene-2-carboxamide (m, 1H), 3.01 (s, 3H), 1.65 (s, 6H), 1.25 (d, 6H, J = 6.0 Hz) 69 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 642 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.68 (s, 1H), 10.14 (trifluoromethoxy)phenyl)pro- (s, 1H), 8.54 (s, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 7.90 (s, pan-2-yl)phenyl)-5- 1H), 7.54 (s, 1H), 7.08 (s, 1H), 6.78 (s, 1H), 6.74 (s, (methylsulfonamido)thieno[2,3- 1H), 6.72 (s, 1H), 4.61~4.67 (m, 1H), 3.07 (s, 3H), 1.65 b]pyridine-2-carboxamide (s, 6H), 1.25 (d, 6H, J = 5.9 Hz) 70 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 642 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.89 (s, 1H), 10.57 (trifluoromethoxy)phenyl)pro- (s, 1H), 8.45 (d, 1H, J = 8.9 Hz), 8.41 (s, 1H), 7.92 (m, pan-2-yl)phenyl)-5- 1H), 7.56 (m, 1H), 7.03~7.06 (m, 2H), 6.77 (s, 1H), 6.72 (methylsulfonamido)thieno[3,2- (m, 1H), 6.71 (s, 1H), 4.60~4.66 (m, 1H), 3.42 (s, 3H), b]pyridine-2-carboxamide 1.64 (s, 6H), 1.23 (d, 6H, J = 6.0 Hz) 71 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 642 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.73 (s, 1H), 10.54 (trifluoromethoxy)phenyl)pro- (brs, 1H), 9.10 (s, 1H), 8.27 (s, 1H), 7.90 (m, 1H), 7.52 pan-2-yl)phenyl)-5- (s, 2H), 7.08 (m, 1H), 6.77 (s, 1H), 6.73 (s, 1H), 6.71 (s, (methylsulfonamido)thieno[2,3- 1H), 4.60~4.66 (m, 1H), 3.31 (s, 3H), 1.64 (s, 6H), 1.24 c]pyridine-2-carboxamide (d, 6H, J = 6.0 Hz) 72 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 655 (M + 1) isobutoxy-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.87 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.6 Hz), 7.90 (s, pan-2-yl)phenyl)-5- 1H), 7.80 (s, 1H), 7.52 (s, 1H), 7.36 (d, 1H, J = 8.8 Hz), (methylsulfonamido)ben- 7.04 (s, 1H), 6.71~6.80 (m, 3H), 3,75 (d, 2H, J = 6.4 Hz), zo[b]thiophene-2-carboxamide 3.01 (s, 3H), 1.93~2.04 (m, 1H), 1.64 (s, 6H), 0.96 (d, 6H, J = 6.6 Hz) 73 N-(3-chloro-5-(2-(3-propoxy-5- LC/MS ESI (+): 641 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 9.89 (s, pan-2-yl)phenyl)-5- 1H), 8.29 (s, 1H), 8.03 (d, 1H, J = 8.8 Hz), 7.91 (s, 1H), (methylsulfonamido)ben- 7.81 (s, 1H), 7.53 (s, 1H), 7.37 (d, 1H, J = 8.8 Hz), 7.05 (s, zo[b]thiophene-2-carboxamide 1H), 6.80 (s, 2H), 6.73 (s, 1H), 3.94 (t, 2H, J = 6.4 Hz), 3.03 (s, 3H), 1.69~1.74 (m, 2H), 1.65 (s, 6H), 0.97 (t, 3H, J = 7.2 Hz) 74 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 625 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.43 (s, 1H), 9.83 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.57 (s, 1H), 8.54 (s, 1H), 8.04 (m, 1H), 7.80 pan-2-yl)phenyl)-6- (m, 1H), 7.64 (d, 1H, J = 9.6 Hz), 7.27 (dd, 1H, J = 9.6, (methylsulfonamido)imidazo[1,2- 1.6 Hz), 6.96 (m, 1H), 6.69 (s, 1H), 6.67 (m, 1H), 6.64 (s, a]pyridine-2-carboxamide 1H), 4.53~4.59 (m, 1H), 3.00 (s, 3H), 1.63 (s, 6H), 1.23 (d, 6H, J = 6.0 Hz) 75 N-(3-(2-(3-(but-2-yn-1- LC/MS ESI (+): 651 (M + 1) yloxy)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.88 (s, (trifluoromethoxy)phenyl)pro- 1H), 8.29 (s, 1H), 8.03 (d, 1H, J = 8.8 Hz), 7.91 (s, 1H), pan-2-yl)-5-chlorophenyl)-5- 7.80 (d, 1H, J = 2.0 Hz), 7.55 (s, 1H), 7.37 (dd, 1H, J = 8.8, (methylsulfonamido)ben- 2.0 Hz), 7.05 (s, 1H), 6.84 (s, 2H), 6.80 (s, 1H), 4.78 (d, zo[b]thiophene-2-carboxamide 2H, J = 2.4 Hz), 3.02 (s, 3H), 1.80 (s, 3H) 1.66 (s, 6H) 76 N-(3-chloro-5-(2-(3-(oxetan- LC/MS ESI (+): 655 (M + 1) 3-yloxy)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.86 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.28(s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.90 (s, pan-2-yl)phenyl)-5- 1H), 7.80 (s, 1H), 7.53 (s, 1H), 7.36(d, 1H, J = 8.7 Hz), (methylsulfonamido)ben- 7.05 (s, 1H), 6.79 (s, 1H), 6.68 (s, 1H), 6.62 (s, 1H), zo[b]thiophene-2-carboxamide 5.30~5.35 (m, 1H), 4.87 (dd, 2H, J = 6.8, 6.4 Hz), 4.51 (dd, 2H, J = 7.2, 4.8 Hz), 3.01 (s, 3H), 1.65 (s, 6H) 77 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 638 (M + 1) (cyanomethoxy)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.85 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.91 (s, pan-2-yl)phenyl)-5- 1H), 7.79 (s, 1H), 7.54 (s, 1H), 7.36 (d, 1H, J = 8.7 Hz), (methylsulfonamido)ben- 7.04 (s, 1H), 7.00 (s, 1H), 6.96 (s, 1H), 6.87 (s, 1H), zo[b]thiophene-2-carboxamide 5.23 (s, 2H), 3.01 (s, 3H), 1.66 (s, 6H) 78 N-(3-(2-(3-(allyloxy)-5- LC/MS ESI (+): 639 (M + 1) (trifluoromethoxy)phenyl)pro- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.87 pan-2-yl)-5-chlorophenyl)-5- (brs, 1H), 8.29 (s, 1H), 8.02 (d, 1H, J = 8.4 Hz), 7.91 (m, (methylsulfonamido)ben- 1H), 7.79 (s, 1H), 7.54 (s, 1H), 7.36 (d, 1H, J = 8.7 Hz), zo[b]thiophene-2-carboxamide 7.05 (m, 1H), 6.83 (s, 2H), 6.75 (s, 1H), 5.96~6.06 (m, 1H), 5.40 (dd, 1H, J = 17.3, 1.6 Hz), 5.27 (dd, 1H, J = 10.8, 1.7 Hz), 4.60 (d, 2H, J = 5.4 Hz), 3.01 (s, 3H), 1.66 (s, 6H) 79 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 639 (M + 1) cyclopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.88 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.29 (s, 1H), 8.03 (d, 1H, J = 8.4 Hz), 7.91 (m, pan-2-yl)phenyl)-5- 1H), 7.80 (m, 1H), 7.55 (s, 1H), 7.37 (dd, 1H, J = 8.8, (methylsulfonamido)ben- 2.4 Hz), 7.06 (m, 1H), 6.95 (s, 1H), 6.87 (m, 1H), 6.78 (s, zo[b]thiophene-2-carboxamide 1H), 3.86~3.91 (m, 1H), 3.02 (s, 3H), 1.66 (s, 6H), 0.78 (m, 2H), 0.67 (m, 2H) 80 N-(3-chloro-5-(2-(3-(1,1,2,2- LC/MS ESI (+): 699 (M + 1) tetrafluoroethoxy)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.88 (s, (trifluoromethoxy)phenyl)pro- 1H), 8.28 (s, 1H), 8.03 (d, 1H, J = 8.4 Hz), 7.93 (s, 1H), pan-2-yl)phenyl)-5- 7.80 (s, 1H), 7.56 (s, 1H), 7.37 (d, 1H, J = 8.8 Hz), 7.27 (s, (methylsulfonamido)ben- 1H), 7.24 (s, 1H), 7.14 (s, 1H), 7.07 (s, 1H), 6.82 (tt, 1H, zo[b]thiophene-2-carboxamide J = 56.0, 3.2 Hz), 3.02 (s, 3H), 1.69 (s, 6H) 81 N-(3-chloro-5-(2-(3- LC/MS ESI(+): 642 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 11.21 (s, 1H), 10.19 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.26 (d, 1H, J = 8.7 Hz), 8.10 (s, 1H), 8.05 (s, pan-2-yl)phenyl)-5- 1H), 7.86 (s, 1H), 7.51 (dd, 1H, J = 8.7, 2.0 Hz), 7.13 (s, (methylsulfonamido)ben- 1H), 6.83 (s, 1H), 6.79 (s, 1H), 6.77 (s, 1H), 4.67~4.70 zo[d]thiazole-2-carboxamide (m, 1H), 3.11 (s, 3H), 1.70 (s, 6H), 1.29 (d, 6H, J = 6.0 Hz) 82 N-(3-fluoro-5-(2-(3- LC/MS ESI (+): 625 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.87 (s, (trifluoromethoxy)phenyl)pro- 1H), 8.29 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.80 (s, 1H), pan-2-yl)phenyl)-5- 7.68 (d, 1H, J = 10.8 Hz), 7.40 (s, 1H), 7.36 (d, 1H, (methylsulfonamido)ben- J = 8.8 Hz), 6.85 (d, 1H, J = 10.4 Hz), 6.76 (s, 1H), 6.73 (s, zo[b]thiophene-2-carboxamide 1H), 6.70 (s, 1H), 4.59~4.65 (m, 1H), 3.01 (s, 3H), 1.64 (s, 6H), 1.23 (d, 6H, J = 6.0 Hz) 83 N-(3-chloro-5-(2-(3-(2,2- LC/MS ESI (+): 663 (M + 1) difluoroethoxy)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.87 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.90 (s, pan-2-yl)phenyl)-5- 1H), 7.79 (s, 1H), 7.53 (s, 1H), 7.36 (d, 1H, J = 8.7 Hz), (methylsulfonamido)ben- 7.04 (s, 1H), 6.92 (s, 1H), 6.89 (s, 1H), 6.80 (s, 1H), zo[b]thiophene-2-carboxamide 6.37 (tt, 1H, J = 54.3, 3.3 Hz), 4.37 (td, 2H, J = 14.7, 3.3 Hz), 3.01 (s, 3H), 1.65 (s, 6H) 84 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 659 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.61 (s, 1H), 9.77 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.29 (s, 1H), 8.09 (d, 1H, J = 10.4 Hz), 7.99 (d, pan-2-yl)phenyl)-6-fluoro-5- 1H, J = 7.6 Hz), 7.90 (m, 1H), 7.53 (s, 1H), 7.06 (m, 1H), (methylsulfonamido)ben- 6.78 (s, 1H), 6.74 (m, 1H), 6.72 (s, 1H), 4.62~4.65 (m, zo[b]thiophene-2-carboxamide 1H), 3.06 (s, 3H), 1.65 (s, 6H), 1.25 (d, 6H, J = 6.0 Hz) 85 N-(3-fluoro-5-(2-(3-(1,1,2,2- LC/MS ESI (+): 683 (M + 1) tetrafluoroethoxy)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.59 (s, 1H), 9.88 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.29 (s, 1H), 8.03 (d, 1H, J = 8.8 Hz), 7.80 (m, pan-2-yl)phenyl)-5- 1H), 7.71 (d, 1H, J = 10.9 Hz), 7.42 (s, 1H), 7.37 (dd, 1H, (methylsulfonamido)ben- J = 8.7, 2.1 Hz), 7.26 (s, 1H), 7.23 (s, 1H), 7.13 (s, 1H), zo[b]thiophene-2-carboxamide 6.89 (d, 1H, J = 10.2 Hz), 6.81 (tt, 1H, J = 51.9, 3.0 Hz), 3.02 (s, 3H), 1.69 (s, 6H) 86 N-(3-fluoro-5-(2-(3-(1,1,2,2- LC/MS ESI (+): 684 (M + 1) tetrafluoroethoxy)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.76 (s, 1H), 10.54 (trifluoromethoxy)phenyl)pro- (s, 1H), 9.10 (s, 1H), 8.27 (s, 1H), 7.70 (d, 1H, pan-2-yl)phenyl)-5- J = 10.9 Hz), 7.52 (s, 1H), 7.41 (s, 1H), 7.26 (s, 1H), 7.23 (methylsulfonamido)thieno[2,3- (s, 1H), 7.13 (s, 1H), 6.93 (d, 1H, J = 10.4 Hz), 6.81 (tt, c]pyridine-2-carboxamide 1H, J = 51.9, 3.0 Hz), 3.31 (s, 3H), 1.69 (s, 6H) 87 N-(3-bromo-5-(2-(3-(1,1,2,2- LC/MS ESI (+): 743 (M + 1) tetrafluoroethoxy)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.88 (s, (trifluoromethoxy)phenyl)pro- 1H), 8.28 (s, 1H), 8.06 (s, 1H), 8.03 (d, 1H, J = 8.8 Hz), pan-2-yl)phenyl)-5- 7.80 (s, 1H), 7.60 (s, 1H), 7.36 (dd, 1H, J = 8.8, 1.6 Hz), (methylsulfonamido)ben- 7.27 (s, 1H), 7.24 (s, 1H), 7.19 (s, 1H), 7.14 (s, 1H), zo[b]thiophene-2-carboxamide 6.82 (tt, 1H, J = 52.0, 3.2 Hz), 3.02 (s, 3H), 1.69 (s, 6H) 88 N-(3-chloro-5-(2-(3-(2,2,2- LC/MS ESI (+): 681 (M + 1) trifluoroethoxy)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.85 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.5 Hz), 7.90 (s, pan-2-yl)phenyl)-5- 1H), 7.79 (s, 1H), 7.55 (s, 1H), 7.36 (d, 1H, J = 8.7 Hz), (methylsulfonamido)ben- 7.05 (s, 1H), 7.00 (s, 1H), 6.98 (s, 1H), 6.84 (s, 1H), zo[b]thiophene-2-carboxamide 4.85 (q, 2H, J = 8.8 Hz), 3.00 (s, 3H), 1.67 (s, 6H) 89 N-(3-bromo-5-(2-(3-(1,1,2,2- LC/MS ESI (+): 744 (M + 1) tetrafluoroethoxy)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.71 (s, 1H), 10.53 (trifluoromethoxy)phenyl)pro- (brs, 1H), 9.10 (s, 1H), 8.26 (s, 1H), 8.04 (s, 1H), 7.57 pan-2-yl)phenyl)-5- (s, 1H), 7.52 (s, 1H), 7.26 (s, 1H), 7.22 (s, 2H), 7.12 (s, (methylsulfonamido)thieno[2,3- 1H), 6.80 (t, 1H, J = 52.0 Hz), 3.33 (s, 3H), 1.68 (s, 6H) c]pyridine-2-carboxamide 90 N-(3-chloro-5-(2-(3-(2- LC/MS ESI (+): 712 (M + 1) morpholinoethoxy)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.91 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.9 Hz), 7.91 (s, pan-2-yl)phenyl)-5- 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.34 (d, 1H, J = 8.9 Hz), (methylsulfonamido)ben- 7.05 (s, 1H), 6.84 (s, 1H), 6.80 (s, 1H), 6.75 (s, 1H), zo[b]thiophene-2-carboxamide 4.10 (t, 2H, J = 5.5 Hz), 3.54~3.57 (m, 4H), 3.05 (s, 3H), 2.65 (t, 2H, J = 5.5 Hz), 2.41~2.46 (m, 4H), 1.65 (s, 6H) 91 N-(3-(2-(3-bromo-5- LC/MS ESI (+): 636 (M + 1) isopropoxyphenyl)propan-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.90 yl)-5-chlorophenyl)-5- (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.91 (s, (methylsulfonamido)ben- 1H), 7.77 (s, 1H), 7.49 (s, 1H), 7.34 (d, 1H, J = 8.7 Hz), zo[b]thiophene-2-carboxamide 7.06 (s, 1H), 6.98 (s, 1H), 6.91 (s, 1H), 6.68 (s, 1H), 4.52~4.64 (m, 1H), 2.99 (s, 3H), 1.64 (s, 6H), 1.21 (d, 6H, J = 6.0 Hz) 92 N-(3-chloro-5-(2-(3-chloro- LC/MS ESI (+): 591 (M + 1) 5-isopropoxyphenyl)propan- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.88 2-yl)phenyl)-5- (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.91 (s, (methylsulfonamido)ben- 1H), 7.77 (s, 1H), 7.49 (s, 1H), 7.34 (d, 1H, J = 8.7 Hz), zo[b]thiophene-2-carboxamide 7.07 (s, 1H), 6.87 (s, 1H), 6.79 (s, 1H), 6.65 (s, 1H), 4.59~4.63 (m, 1H), 3.00 (s, 3H), 1.62 (s, 6H), 1.22 (d, 6H, J = 6.0 Hz) 93 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 659 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.67 (s, 1H), 9.75 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.46 (s, 1H), 7.89~7.92 (m, 2H), 7.49~7.53 pan-2-yl)phenyl)-4-fluoro-5- (m, 2H), 7.06 (m, 1H), 6.78 (s, 1H), 6.71~6.72 (m, 2H), (methylsulfonamido)ben- 4.60~4.66 (m, 1H), 3.05 (s, 3H), 1.64 (s, 6H), 1.23 (d, zo[b]thiophene-2-carboxamide 6H, J = 6.0 Hz) 94 N-(3-chloro-5-(2-(3-(2- LC/MS ESI (+): 670 (M + 1) (dimethylamino)ethoxy)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.88 (s, (trifluoromethoxy)phenyl)pro- 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.90 (s, 1H), pan-2-yl)phenyl)-5- 7.79 (d, 1H J = 2.0 Hz), 7.52 (s, 1H), 7.35 (dd, 1H, J = 8.8, (methylsulfonamido)ben- 2.0 Hz), 7.05 (s, 1H), 6.82 (s, 1H), 6.78 (s, 1H), 6.73 (s, zo[b]thiophene-2-carboxamide 1H), 4.04 (t, 2H J = 5.6 Hz), 3.01 (s, 3H), 2.57 (t, 2H J = 5.6 Hz), 2.17 (s, 6H), 1.64 (s, 6H) 95 tert-butyl 4-(3-(2-(3-chloro-5-(5- LC/MS ESI (+): 782 (M + 1) (methylsulfonamido)ben- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.90 (s, zo[b]thiophene-2- 1H), 8.29 (s, 1H), carboxamido)phenyl)propan- 8.03 (d, 1H, J = 8.8 Hz), 7.90 (s, 1H), 7.80 (s, 1H), 7.55 (s, 2-yl)-5- 1H), 7.36 (d, 1H, J = 8.8 Hz), 7.07 (s, 1H), 6.90 (s, 1H), (trifluoromethoxy)phenoxy)pi- 6.80 (s, 1H), 6.75 (s, 1H), 4.60~4.62 (m, 1H), 3.64~3.67 peridine-1-carboxylate (m, 2H), 3.10~3.20 (m, 2H), 3.02 (s, 3H), 1.86~1.91 (m, 2H), 1.65 (s, 6H), 1.53~1.44 (m, 2H), 1.39 (s, 9H) 96 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 682 (M + 1) (piperidin-4-yloxy)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 8.26 (s, (trifluoromethoxy)phenyl)pro- 1H), 7.99 (d, 1H, J = 8.8 Hz), 7.90 (s, 1H), 7.76 (s, 1H), pan-2-yl)phenyl)-5- 7.53 (s, 1H), 7.33 (d, 1H, J = 8.8 Hz), 7.05 (s, 1H), 6.82 (s, (methylsulfonamido)ben- 1H), 6.74 (s, 1H), 6.71 (s, 1H), 4.37~4.46 (m, 1H), 2.98 zo[b]thiophene-2-carboxamide (s, 3H), 2.88~2.92 (m, 2H), 2.53~2.57 (m, 2H), 1.84~1.89 (m, 2H), 1.64 (s, 6H), 1.38~1.42 (m, 2H) 97 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 631 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.29 (s, 1H), 7.86 (m, (trifluoromethoxy)phenyl)pro- 1H), 7.76 (s, 1H), 7.45 (s, 1H), 7.01 (m, 1H), 6.77 (s, pan-2-yl)phenyl)-5- 1H), 6.71 (s, 1H), 6.69 (s, 1H), 4.59~4.65 (m, 1H), 4.32 (methylsulfonyl)-4,5,6,7- (s, 2H), 3.49~3.52 (m, 2H), 2.98 (s, 5H), 1.62 (s, 6H), tetrahydrothieno[3,2- 1.23 (d, 6H, J = 6.0 Hz) c]pyridine-2-carboxamide 98 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 641(M + 1) methoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 11.97 (s, 1H), 10.40 (trifluoromethoxy)phenyl)pro- (brs, 2H), 8.75 (s, 1H), 8.07 (s, 1H), 7.59 (s, 1H), 7.49 pan-2-yl)phenyl)-6- (s, 1H), 7.15 (s, 1H), 7.07 (s, 1H), 6.82 (s, 1H), 6.80 (s, (methylsulfonamido)-1H- 1H), 6.73 (s, 1H), 3.78 (s, 3H), 3.24 (s, 3H), 1.64 (s, 6H) pyrrolo[3,2-c]pyridine-2- carboxamide 99 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 641 (M + 1) methoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 12.18 (s, 1H), 10.49 (trifluoromethoxy)phenyl)pro- (s, 1H), 9.95 (s, 1H), 8.60 (s, 1H), 8.07 (s, 1H), 7.59 (s, pan-2-yl)phenyl)-5- 1H), 7.34 (s, 1H), 7.32 (s, 1H), 7.18 (s, 1H), 6.81 (s, (methylsulfonamido)-1H- 2H), 6.73 (s, 1H), 3.77 (s, 3H), 3.19 (s, 3H), 1.65 (s, 6H) pyrrolo[2,3-c]pyridine-2- carboxamide 2,2,2- trifluoroacetate 100 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 625 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 12.12 (s, 1H), 10.63 (trifluoromethoxy)phenyl)pro- (brs, 1H), 10.22 (s, 1H), 8.04 (d, 1H, J = 8.4 Hz), 7.95 (s, pan-2-yl)phenyl)-6- 1H), 7.53 (s, 1H), 7.31 (s, 1H), 7.00 (s, 1H), 6.71~6.77 (methylsulfonamido)-1H- (m, 4H), 4.61~4.64 (m, 1H), 3.43 (s, 3H), 1.64 (s, 6H), pyrrolo[2,3-b]pyridine-2- 1.23 (d, 6H, J = 5.9 Hz) carboxamide 101 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 625 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 11.98 (brs, 1H), 10.41 (trifluoromethoxy)phenyl)pro- (brs, 2H), 8.75 (s, 1H), 7.94(s, 1H), 7.54 (s, 1H), 7.48 (s, pan-2-yl)phenyl)-6- 1H), 7.07 (s, 1H), 7.03(s, 1H), 6.77 (s, 1H), 6.73 (s, 1H), (methylsulfonamido)-1H- 6.71 (s, 1H), 4.61~4.64 (m, 1H), 3.23 (s, 3H), 1.64 (s, pyrrolo[3,2-c]pyridine-2- 6H), 1.23 (d, 6H, J = 5.5 Hz) carboxamide 102 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 591 (M + 1) isopropoxy-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.43 (s, 1H), 9.98 (trifluoromethoxy)phenyl)pro- (brs, 1H), 7.85 (s, 2H), 7.50 (s, 1H), 7.33 (s, 1H), 7.01 pan-2-yl)phenyl)-4- (s, 1H), 6.69~6.76 (m, 2H), 4.60~4.66 (m, 2H), 3.02 (s, (methylsulfonamido)thio- 3H), 1.64 (s, 6H), 1.24 (d, 6H, J = 5.9 Hz) phene-2-carboxamide 103 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 712 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 10.19 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.27 (s, 1H), 8.00 (d, 1H, J = 8.8 Hz), 7.91 (s, pan-2-yl)phenyl)-5- 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.36 (dd, 1H, J = 8.7, (morpholine-4- 2.1 Hz), 7.05 (s, 1H), 6.77 (s, 1H), 6.72 (s, 1H), 6.71 (s, sulfonamido)benzo[b]thio- 1H), 4.60~4.66 (m, 1H), 3.51~3.54 (m, 4H), 3.07~3.10 phene-2-carboxamide (m, 4H), 1.64 (s, 6H), 1.23 (d, 6H, J = 6.0 Hz) 104 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 646 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.21 (s, 1H), 8.55 (s, (trifluoromethoxy)phenyl)pro- 1H), 7.86 (m, 1H), 7.68 (s, 1H), 7.48 (m, 1H), 6.99 (m, pan-2-yl)phenyl)-5- 1H), 6.76 (s, 1H), 6.71 (m, 1H), 6.69 (s, 1H), 4.62 (m, (methylsulfonamido)-4,5,6,7- 1H), 3.93 (s, 2H), 3.12~3.15 (m, 2H), 2.97~3.00 (m, tetrahydrothieno[3,2- 5H), 1.62 (s, 6H), 1.23 (d, 6H, J = 6.0 Hz) c]pyridine-2-carboxamide 105 6-chloro-N-(3-chloro-5-(2- LC/MS ESI (+): 675 (M + 1) (3-isopropoxy-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.64 (s, m), 9.68 (trifluoromethoxy)phenyl)pro- (brs, 1H), 8.34 (s, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 7.89 pan-2-yl)phenyl)-5- (s, 1H), 7.52 (s, 1H), 7.05 (s, 1H), 6.77 (s, 1H), 6.72 (s, (methylsulfonamido)ben- 1H), 6.70 (s, 1H), 4.60 (m, 1H), 3.05 (s, 3H), 1.64 (s, zo[b]thiophene-2-carboxamide 6H), 1.23 (d, 6H, J = 5.9 Hz) 106 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 529 (M + 1) methoxyphenyl)propan-2- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.46 (s, 1H), 9.79 yl)phenyl)-5- (brs, 1H), 8.21 (s, 1H), 7.95 (d, 1H, J = 8.8 Hz), 7.81 (s, (methylsulfonamido)ben- 1H), 7.72 (s, 1H), 7.46 (s, 1H), 7.29 (dd, 1H, J = 8.8, zo[b]thiophene-2-carboxamide 2.0 Hz), 7.16 (t, 1H, J = 8.8 Hz), 6.94 (s, 1H), 6.10~6.73 (m, 3H), 3.66 (s, 3H), 2.94 (s, 3H), 1.57 (s, 6H)

Example 107 Synthesis of N-(3-ethynyl-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of N-(3-(2-(4-fluorophenyl)propan-2-yl)-5-((trimethylsilyl)ethynyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

N-(3-bromo-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (56.0 mg, 0.10 mmol), CuI (12.0 mg, 0.06 mmol), and Pd(t-Bu₃P)₂ (31.0 mg, 0.06 mmol) were dried under reduced pressure, and dissolved in anhydrous 1,4-dioxane (1.0 mL) in a sealed tube. Ethynyltrimethylsilane (189.0 μL, 1.34 mmol), Et₃N (186.0 μL, 1.34 mmol) were added, followed by heating at 130° C. for 14 hours, and the reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and then extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=20:1) to obtain N-(3-(2-(4-fluorophenyl)propan-2-yl)-5-((trimethylsilyl)ethynyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (30.0 mg, 50%) as an off-white solid.

LC/MS ESI (+): 562 (M+1)

(b) Synthesis of N-(3-ethynyl-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

To a solution of N-(3-(2-(4-fluorophenyl)propan-2-yl)-5-((trimethylsilyl)ethynyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (30.0 mg, 0.05 mmol) in anhydrous THF (1.0 mL), 1 N solution of TBAF in THF (106.0 μL, 0.10 mol) was added, followed by stirring at room temperature for 1 hour. Water was added, and then extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=20:1) to obtain N-(3-ethynyl-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (10.0 mg, 38%) as an off-white solid.

LC/MS ESI (+): 490 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): 0.3-11.68 (s, 1H), 10.15 (s, 1H), 9.58 (brs, 1H), 7.92 (s, 1H), 7.60-7.64 (m, 2H), 7.38 (d, 1H, J=1.3 Hz), 7.36 (d, 1H, J=1.3 Hz), 7.24-7.30 (m, 2H), 7.09-7.16 (m, 2H), 7.03 (s, 1H), 6.98 (dd, 1H, J=8.2, 1.5 Hz), 4.15 (s, 1H), 2.84 (s, 3H), 1.65 (s, 6H)

Through the synthetic method according to Example 107, compounds of Example 108 and Example 109 were synthesized, and the data of each example are as follows.

TABLE 3 Ex. Compound Analysis data 108 N-(3-ethynyl-5-(2-(4- LC/MS ESI (+): 507 (M + 1) fluorophenyl)propan-2-yl)phenyl)-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.48 (s, (methylsulfonamido)benzo[b]thiophene- 1H), 9.88 (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, 2-carboxamide J = 8.8 Hz), 7.87 (s, 1H), 7.78 (d, 1H, J = 1.9 Hz), 7.61 (s, 1H), 7.35 (dd, 1H, J = 8.8, 1.9 Hz), 7.25~7.29 (m, 2H), 7.07~7.15 (m, 3H), 4.20 (s, 1H), 3.00 (s, 3H), 1.64 (s, 6H) 109 N-(3-(2-(2,4-difluorophenyl)propan-2- LC/MS ESI (+): 525 (M + 1) yl)-5-ethynylphenyl)-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.43 (s, (methylsulfonamido)benzo[b]thiophene- 1H), 9.83 (brs, 1H), 8.26 (s, 1H), 8.01 (d, 1H, 2-carboxamide J = 8.6 Hz), 7.86 (t, 1H, J = 1.5 Hz), 7.78 (d, 1H, J = 1.9 Hz), 7.56~7.64 (m, 2H), 7.35 (dd, 1H, J = 8.8, 2.1 Hz), 7.06~7.16 (m, 2H), 7.02 (s, 1H), 4.15 (s, 1H), 3.01 (s, 3H), 1.65 (s, 6H)

Example 110 Synthesis of 3-chloro-N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 3-chloro-N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-nitrobenzo[b]thiophene-2-carboxamide

3-Chloro-6-nitrobenzo[b]thiophene-2-carboxylic acid (50.0 mg, 0.19 mmol), 3-(2-(4-fluorophenyl)propan-2-yl)aniline (49.0 mg, 0.21 mmol), HATU (81.0 mg, 0.21 mmol), and DIPEA (51.0 μL, 0.29 mmol) were dissolved in anhydrous DMF (4.0 mL), followed by heating at 40° C. for 24 hours. The reaction mixture was extracted with EtOAc, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=4:1) to obtain 3-chloro-N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-nitrobenzo[b]thiophene-2-carboxamide (37.0 mg, 41%) as a yellowish brown solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 10.69 (s, 1H), 9.28 (s, 1H), 8.39 (dd, 1H, J=8.8, 2.2 Hz), 8.13 (d, 1H, J=8.8 Hz), 7.57-7.61 (m, 2H), 7.10-7.34 (m, 3H), 6.34-6.39 (m, 3H), 1.64 (s, 6H)

(b) Synthesis of 6-amino-3-chloro-N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide

3-Chloro-N-(3 fluorophenyl)propan-2-yl)phenyl)-6-nitrobenzo[b]thiophene-2-carboxamide (35.0 mg, 0.08 mmol), Zn (73.6 mg, 1.13 mmol), and NH₄Cl (20.0 mg, 0.38 mmol) were dissolved in a mixture of THF/MeOH/H₂O (3.0 mL, 1/0.5/0.5 v/v), and ultrasonificated for 1.5 hours. Through filtering and concentration under reduced pressure, 6-amino-3-chloro-N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide was obtained as a white solid.

LC/MS ESI (+): 439 (M+1)

(c) Synthesis of 3-chloro-N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

6-Amino-3-chloro-N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide was dissolved in pyridine (1.0 mL), and methanesulfonyl chloride (7.6 μL, 0.10 mmol) was slowly added at 0° C. The reaction mixture was stirred at room temperature for 2 hours and extracting with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=20:1) to obtain 3-chloro-N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (20.9 mg, 2 step yield: 54%) as a white solid.

LC/MS ESI (+): 517 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 10.40 (s, 1H), 10.24 (s, 1H), 7.90 (m, 1H), 7.88 (d, 1H, J=8.8 Hz), 7.56-7.60 (m, 2H), 7.42 (dd, 1H, J=8.8, 1.9 Hz), 7.23-7.31 (m, 3H), 7.07-7.13 (m, 2H), 7.00 (d, 1H, J=7.6 Hz), 3.11 (s, 3H), 1.63 (s, 6H)

Through the synthetic method according to Example 110, compounds from Example 111 to Example 113 were synthesized, and the data of each example are as follows.

TABLE 4 Ex. Compound Analysis data 111 3-chloro-N-(2′,4′-difluoro- LC/MS ESI (+): 493 (M + 1) [1,1′-biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.56 (s, 1H), 10.28 (methylsulfonamido)ben- (s, 1H), 7.88~7.93 (m, 3H), 7.75 (d, 1H, J = 8.5 Hz), zo[b]thiophene-2-carboxamide 7.56~7.64 (m, 1H), 7.50 (t, 1H, J = 7.7 Hz), 7.36~7.44 (m, 2H), 7.31 (d, 1H, J = 7.7 Hz), 7.19~7.25 (m, 1H), 3.10 (s, 3H) 112 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 473 (M + 1) biphenyl]-3-yl)-7-methoxy- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.59 (s, 1H), 9.72 5-(methylsulfonamido)benzo- (brs, 1H), 7.99 (s, 1H), 7.87 (d, 1H, J = 8.1 Hz), 7.75 (s, furan-2-carboxamide 1H), 7.56~7.64 (m, 1H), 7.48 (t, 1H, J = 8.1 Hz), 7.36~7.44 (m, 1H), 7.28~7.30 (m, 1H), 7.22~7.26 (m, 1H), 7.20 (s, 1H), 6.90 (s, 1H), 3.97 (s, 3H), 3.00 (s, 3H) 113 N-(3-(2-(4- LC/MS ESI (+): 497 (M + 1) fluorophenyl)propan-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.39 (s, 1H), 9.71 yl)phenyl)-7-methoxy-5- (brs, 1H), 7.73 (d, 1H, J = 7.6 Hz), 7.70 (s, 1H), 7.63 (s, (methylsulfonamido)benzo- 1H), 7.23~7.30 (m, 3H), 7.18 (m, 1H), 7.07~7.13 (m, furan-2-carboxamide 2H), 6.98 (d, 1H, J = 8.0 Hz), 6.94 (s, 1H), 3.95 (s, 3H), 2.99 (s, 3H), 1.64 (s, 6H)

Example 114 Synthesis of N-(3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-(trifluoromethoxy)phenyl trifluoromethanesulfonate

3-(2-(3-Chloro-5-nitrophenyl)propan-2-yl)-5-(trifluoromethoxy)phenol (100.0 mg, 0.27 mmol) was dissolved in CH₂Cl₂ (2.7 mL), and pyridine (109.0 μL, 1.35 mmol) and Tf₂O (45.0 μL, 0.27 mmol) were slowly added at 0° C. The mixture was stirred at 0° C. for 2 hours and then extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-(trifluoromethoxy)phenyl trifluoromethanesulfonate (120.0 mg, 88%) as a colorless liquid.

¹H-NMR (400 MHz, CDCl₃): δ 8.13 (t, 1H, J=1.9 Hz), 7.99 (t, 1H, J=1.9 Hz), 7.45 (t, 1H, J=1.8 Hz), 7.08-7.10 (m, 2H), 7.04 (t, 1H, J=1.9 Hz), 1.75 (s, 6H)

(b) Synthesis of 1-chloro-3-nitro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)benzene

3-(2-(3-Chloro-5-nitrophenyl)propan-2-yl)-5-(trifluoromethoxy)phenyl trifluoromethanesulfonate (280.0 mg, 0.55 mmol) was dissolved in anhydrous DMF (5.5 mL), and 1-(trimethylsilyl)-1-propyne (123.0 μL, 0.83 mmol), Pd(PPh₃)₄ (64.0 mg, 0.06 mmol), CuI (21.0 mg, 0.11 mmol), and DIPEA (480.0 μL, 2.75 mmol) were added at room temperature. The mixture was heated at 90° C. for 15 hours and then extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:CH₂Cl₂=4:1) to obtain 1-chloro-3-nitro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)benzene (120.0 mg, 55%) as a colorless liquid.

¹H-NMR (400 MHz, CDCl₃): δ 8.08 (t, 1H, J=1.9 Hz), 7.99 (t, 1H, J=1.9 Hz), 7.46 (t, 1H, J=1.8 Hz), 7.11-7.13 (m, 2H), 6.94 (s, 1H), 2.04 (s, 3H), 1.70 (s, 6H)

(c) Synthesis of 3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)aniline

The synthesis procedure of Intermediate 40 was repeated except for using 1-chloro-3-nitro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)benzene (120.0 mg, 0.30 mmol) to obtain 3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)aniline (93.0 mg, 84%).

LC/MS ESI (+): 368 (M+1)

(d) Synthesis of N-(3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)aniline (55.0 mg, 0.15 mmol) to obtain N-(3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (40.0 mg, 43%).

LC/MS ESI (+): 621 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.90 (brs, 1H), 8.27 (s, 1H), 8.01 (d, 1H, J=8.6 Hz), 7.92 (s, 1H), 7.78 (s, 1H), 7.52 (s, 1H), 7.35 (d, 1H, J=8.6 Hz), 7.20-7.36 (m, 3H), 7.07 (s, 1H), 2.99 (s, 3H), 2.04 (s, 3H), 1.67 (s, 6H)

Example 115 Synthesis of N-(3-bromo-5-(2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of (3-(2-(3-bromo-5-nitrophenyl)propan-2-yl)phenyl)methanol

Methyl 3-(2-(3-bromo-5-nitrophenyl)propan-2-yl)benzoate (100.0 mg, 0.26 mmol) was dissolved in anhydrous THF (2.6 mL), and LiAlH₄ (15.0 mg, 0.40 mmol) or 1.0 M solution of DIBAL in THF (400.0 μL, 0.40 mmol) was added at 0° C. The mixture was stirred at 0° C. for 1 hour and then extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain (3-(2-(3-bromo-5-nitrophenyl)propan-2-yl)phenyl)methanol (52.0 mg, 56%) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ 8.21 (s, 1H), 8.05 (s, 1H), 7.65 (s, 1H), 7.32 (t, 1H, J=7.6 Hz), 7.21-7.26 (m, 2H), 7.10 (d, 1H, J=7.8 Hz), 4.89 (d, 2H, J=5.9 Hz), 1.73 (s, 6H)

(b) Synthesis of 3-(2-(3-bromo-5-nitrophenyl)propan-2-yl)benzyl methanesulfonate

(3-(2-(3-Bromo-5-nitrophenyl)propan-2-yl)phenyl)methanol (40.0 mg, 0.11 mmol) was dissolved in anhydrous CH₂Cl₂ (1.1 mL), and methanesulfonyl chloride (10.0 μL, 0.13 mmol) and DIPEA (40.0 μL, 0.23 mmol) were added at room temperature. The mixture was stirred at room temperature for 3 hours and then extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 3-(2-(3-bromo-5-nitrophenyl)propan-2-yl)benzyl methanesulfonate (20.0 mg, 41%) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ 8.22 (s, 1H), 8.01 (s, 1H), 7.64 (s, 1H), 7.37 (t, 1H, J=7.6 Hz), 7.31 (d, 1H, J=7.6 Hz), 7.25 (s, 1H), 7.22 (d, 1H, J=7.7 Hz), 4.89 (s, 2H), 2.92 (s, 3H), 1.73 (s, 6H)

(c) Synthesis of 1-(3-(2-(3-bromo-5-nitrophenyl)propan-2-yl)benzyl)-4-methylpiperazine

3-(2-(3-Bromo-5-nitrophenyl)propan-2-yl)benzyl methanesulfonate (20.0 mg, 0.05 mmol) was dissolved in anhydrous CH₂Cl₂ (0.5 mL), and 1-methylpiperazine (10.0 μL, 0.09 mmol) and DIPEA (24.0 μL, 0.14 mmol) were added at room temperature. The mixture was stirred at room temperature for 15 hours and extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH₂Cl₂:MeOH=20:1) to obtain 1-(3-(2-(3-bromo-5-nitrophenyl)propan-2-yl)benzyl)-4-methylpiperazine (22.0 mg, quant.) as a colorless liquid.

¹H-NMR (400 MHz, CDCl₃): δ 8.20 (s, 1H), 8.04 (s, 1H), 7.64 (s, 1H), 7.26 (t, 1H, J=7.6 Hz), 7.19 (d, 1H, J=7.6 Hz), 7.07-7.11 (m, 2H), 3.48 (s, 2H), 2.43 (brs, 8H), 2.28 (s, 3H), 1.72 (s, 6H)

(d) Synthesis of 3-bromo-5-(2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)propan-2-yl)aniline

The synthesis procedure of Intermediate 40 was repeated except for using 1-(3-(2-(3-bromo-5-nitrophenyl)propan-2-yl)benzyl)-4-methylpiperazine (35.0 mg, 0.08 mmol) to obtain 3-bromo-5-(2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)propan-2-yl)aniline (30.0 mg, 92%).

LC/MS ESI (+): 402 (M+1)

(e) Synthesis of N-(3-bromo-5-(2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-bromo-5-(2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)propan-2-yl)aniline (30.0 mg, 0.07 mmol) to obtain N-(3-bromo-5-(2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (2.5 mg, 6%).

LC/MS ESI (+): 655 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.89 (s, 1H), 8.29 (s, 1H), 8.04 (d, 1H, J=8.7 Hz), 7.96 (s, 1H), 7.79 (d, 1H, J=1.6 Hz), 7.62 (s, 1H), 7.36 (dd, 1H, J=8.7, 1.9 Hz), 7.30 (t, 1H, J=7.2 Hz), 7.10-7.19 (m, 4H), 3.51 (s, 2H), 3.02 (s, 3H), 2.70 (brs, 4H), 2.26 (brs, 4H), 1.65 (s, 3H), 1.23 (s, 6H)

Through the synthetic method according to Example 115, compounds from Example 116 to Example 125 were synthesized, and the data of each example are as follows.

TABLE 5 Ex. Compound Analysis data 116 tert-butyl 4-(3-(2-(3-bromo- LC/MS ESI (+): 741 (M + 1) 5-(5-(methylsulfonamido)ben- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.50 (s, 1H), 9.34 zo[b]thiophene-2- (brs, 1H), 8.24 (s, 1H), 7.98 (s, 1H), 7.94 (d, 1H, carboxamido)phenyl)pro- J = 8.8 Hz), 7.72 (s, 1H), 7.61 (s, 1H), 7.38~7.45 (m, 1H), pan-2-yl)benzyl)piperazine-1- 7.26~7.31 (m, 2H), 7.09~7.19 (m, 3H), 3.46 (s, 2H), 3.25 carboxylate (brs, 4H), 2.94 (s, 3H), 2.25 (brs, 4H), 1.64 (s, 6H), 1.34 (s, 9H) 117 tert-butyl 4-(3-(2-(3-bromo- LC/MS ESI (+): 724 (M + 1) 5-(6-(methylsulfonamido)- ¹H-NMR (400 MHz, DMSO-d₆): δ 11.72 (s, 1H), 10.24 (s, 1H-indole-2- 1H), 9.65 (brs, 1H), 8.06 (s, 1H), 7.60~7.62 (m, 2H), carboxamido)phenyl)pro- 7.31~7.43 (m, 6H), 7.05 (s, 1H), 6.97 (d, 1H, J = 8.6 Hz), pan-2-yl)benzyl)piperazine-1- 3.71 (s, 2H), 3.24 (brs, 4H), 2.93 (s, 3H), 2.67 (brs, 4H), carboxylate 1.65 (s, 6H), 1.35 (s, 9H) 118 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 641 (M + 1) (piperazin-1- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 8.28 (s, ylmethyl)phenyl)propan-2- 1H), 7.99~8.03 (m, 2H), 7.78 (s, 1H), 7.59 (s, 1H), 7.35 yl)phenyl)-5- (dd, 1H, J = 8.8, 1.9 Hz), 7.27 (t, 1H, J = 7.8 Hz), 7.16 (d, (methylsulfonamido)ben- 1H, J = 7.8 Hz), 7.09~7.12 (m, 3H), 3.50 (s, 2H), 3.00 (s, zo[b]thiophene-2-carboxamide 3H), 2.66 (brs, 4H), 2.24 (brs, 4H), 1.64 (s, 6H) 119 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 624 (M + 1) (piperazin-1- ¹H-NMR (400 MHz, DMSO-d₆): δ 11.70 (s, 1H), 10.22 (s, ylmethyl)phenyl)propan-2- 1H), 9.65 (brs, 1H), 8.04 (s, 1H), 7.57~7.66 (m, 2H), yl)phenyl)-6- 7.36~7.39 (m, 2H), 6.96~7.28 (m, 6H), 3.44 (s, 2H), 2.93 (methylsulfonamido)-1H- (s, 3H), 2.81 (brs, 4H), 2.30 (brs, 4H), 1.64 (s, 6H) indole-2-carboxamide 120 N-(3-(2-(3-((1H-imidazol- LC/MS ESI (+): 623 (M + 1) 1-yl)methyl)phenyl)propan- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.82 (brs, 2-yl)-5-bromophenyl)-5- 1H), 8.28 (s, 1H), 8.00~8.03 (m, 2H), 7.79 (d, 1H, (methylsulfonamido)ben- J = 1.9 Hz), 7.73 (s, 1H), 7.58 (s, 1H), 7.35 (dd, 1H, J = 8.7, zo[b]thiophene-2-carboxamide 2.1 Hz), 7.29 (t, 1H, J = 7.1 Hz), 7.25 (s, 1H), 7.16~7.17 (m, 2H), 7.10 (s, 1H), 7.02 (d, 1H, J = 7.6 Hz), 6.88 (s, 1H), 5.17 (s, 2H), 3.00 (s, 3H), 1.63 (s, 6H) 121 N-(3-chloro-5-(2-(3-((2- LC/MS ESI (+): 642 (M + 1) hydroxyazetidin-1- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 10.19 yl)methyl)-5- (brs, 1H), 8.27(s, 1H), 7.90 (d, 1H, J = 8.7 Hz), 7.86 (s, isopropoxyphenyl)propan- 1H), 7.76 (s, 1H), 7.55 (s, 1H), 7.33 (dd, 1H, J = 8.7, 2.0 2-yl)phenyl)-5- Hz), 7.07 (s, 1H), 6.98~7.90 (m, 2H), 6.72 (s, 1H), (methylsulfonamido)ben- 4.48~4.54 (m, 1H), 4.21~4.27 (m, 3H), 3.70~3.78 (m, zo[b]thiophene-2-carboxamide 2H), 2.97 (s, 3H), 1.90~2.30 (m, 3H), 1.62 (s, 6H), 1.20 (d, 6H, J = 6.0 Hz) 122 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 700 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.51 (s, 1H), 9.87 (brs, (morpholinomethyl)phenyl)pro- 1H), 8.27 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.98 (m, 1H), pan-2-yl)phenyl)-5- 7.78 (d, 1H, J = 2.0 Hz), 7.58 (m, 1H), 7.35 (dd, 1H, J = 8.7, (methylsulfonamido)ben- 2.1 Hz), 7.11 (m, 1H), 6.66~6.68 (m, 2H), 6.62 (m, 1H), zo[b]thiophene-2-carboxamide 4.55 (m, 1H), 3.50~3.52 (m, 4H), 3.37 (s, 2H), 3.00 (s, 3H), 2.29 (brs, 4H), 1.61 (s, 6H), 1.23 (d, 6H, J = 6.0 Hz) 123 tert-butyl 4-(3-(2-(3-bromo- LC/MS ESI (+): 799 (M + 1) 5-(5-(methylsulfonamido)ben- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.51 (s, 1H), 9.97 (brs, zo[b]thiophene-2- 1H), 8.26 (s, 1H), 7.97~7.99 (m, 2H), 7.75 (s, 1H), 7.60 carboxamido)phenyl)pro- (s, 1H), 7.33 (d, 1H, J = 8.9 Hz), 7.11 (s, 1H), 6.66~6.68 pan-2-yl)-5- (m, 2H), 6.63 (s, 1H), 4.56 (m, 1H), 3.41 (s, 2H), 3.26 isopropoxybenzyl)piperazine- (brs, 4H), 2.97 (s, 3H), 2.25 (brs, 4H), 1.61 (s, 6H), 1.34 1-carboxylate (s, 9H), 1.24 (d, 6H, J = 5.8 Hz) 124 N-(3-bromo-5-(2-(3- LC/MS ESI (+): 699 (M + 1) isopropoxy-5-(piperazin-1- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.52 (s, 1H), 8.28 (s, ylmethyl)phenyl)propan-2- 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.99 (m, 1H), 7.79 (d, 1H, yl)phenyl)-5- J = 1.9 Hz), 7.59 (m, 1H), 7.36 (dd, 1H, J = 8.7, 2.1 Hz), 7.10 (methylsulfonamido)ben- (m, 1H), 6.66~6.68 (m, 2H), 6.62 (m, 1H), 4.55 (m, 1H), zo[b]thiophene-2-carboxamide 3.51 (s, 1H), 3.38 (s, 2H), 3.01 (s, 3H), 2.71~2.74 (m, 4H), 2.29 (brs, 4H), 1.61 (s, 6H), 1.24 (d, 6H, J = 5.9 Hz) 125 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 640 (M + 1) isopropoxy-5-(pyrrolidin-1- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.86 (brs, ylmethyl)phenyl)propan-2- 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.86 (s, 1H), yl)phenyl)-5- 7.79 (s, 1H), 7.55 (s, 1H), 7.36 (dd, 1H, J = 8.4, 1.6 Hz), (methylsulfonamido)ben- 6.99 (s, 1H), 6.70 (m, 2H), 6.61 (m, 1H), 4.54~4.57 (m, zo[b]thiophene-2-carboxamide 1H), 3.48~3.52 (m, 4H), 3.02 (s, 3H), 2.38~2.40 (m, 2H), 1.62~1.66 (m, 10H), 1.24 (d, 6H, J = 5.6 Hz)

Example 126 Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(morpholinomethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 1-(bromomethyl)-3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-isopropoxybenzene

1-Chloro-3-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)-5-nitrobenzene (500.0 mg, 1.44 mmol) was dissolved in anhydrous CCl₄ (15.0 mL), and NBS (256.0 mg, 1.44 mmol) and AIBN (24.0 mg, 0.14 mmol) were added at room temperature. The mixture was refluxed at 90° C. for 3 hours, followed by cooling to room temperature and extracting with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 1-(bromomethyl)-3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-isopropoxybenzene (310.0 mg, 51%) as a yellow liquid.

¹H-NMR (400 MHz, CDCl₃): δ 8.05 (t, 1H, J=1.9 Hz), 8.00 (t, 1H, J=1.9 Hz), 7.49 (t, 1H, J=1.8 Hz), 6.79 (s, 1H), 6.75 (s, 1H), 6.62 (s, 1H), 4.48-4.55 (m, 1H), 4.42 (s, 2H), 1.69 (s, 6H), 1.32 (d, 6H, J=6.0 Hz)

(b) Synthesis of 4-(3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-isopropoxybenzyl)morpholine

1-(Bromomethyl)-3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-isopropoxybenzene (86.0 mg, 0.20 mmol) was dissolved in anhydrous CH₂Cl₂ (3.1 mL), and morpholine (54.0 μL, 0.62 mmol) and DIPEA (162.0 μL, 0.93 mmol) were added at room temperature. The mixture was stirred at room temperature for 2 hours and extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=7:3) to obtain 4-(3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-isopropoxybenzyl)morpholine (66.0 mg, 76%) as a colorless liquid.

¹H-NMR (400 MHz, CDCl₃): δ 8.04 (t, 1H, J=1.9 Hz), 7.99 (t, 1H, J=1.9 Hz), 7.49 (t, 1H, J=1.8 Hz), 6.76 (s, 1H), 6.66 (s, 1H), 6.62 (s, 1H), 4.48-4.58 (m, 1H), 3.68 (t, 4H, J=4.6 Hz), 3.43 (s, 2H), 2.40 (t, 4H, J=4.3 Hz), 1.69 (s, 6H), 1.32 (d, 6H, J=6.0 Hz)

(c) Synthesis of 3-chloro-5-(2-(3-isopropoxy-5-(morpholinomethyl)phenyl)propan-2-yl)aniline

The synthesis procedure of Intermediate 40 was repeated except for using 4-(3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-isopropoxybenzyl)morpholine (66.0 mg, 0.15 mmol) to obtain 3-chloro-5-(2-(3-isopropoxy-5-(morpholinomethyl)phenyl)propan-2-yl)aniline (61.0 mg, quant.).

LC/MS ESI (+): 403 (M+1)

(d) Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(morpholinomethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-chloro-5-(2-(3-isopropoxy-5-(morpholinomethyl)phenyl)propan-2-yl)aniline (61.0 mg, 0.15 mmol) to obtain N-(3-chloro-5-(2-(3-isopropoxy-5-(morpholinomethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (35.0 mg, 36%).

LC/MS ESI (+): 656 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.89 (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J=8.7 Hz), 7.87 (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.35 (d, 1H, J=8.7 Hz), 7.00 (s, 1H), 6.63-6.69

(m, 3H), 4.54-4.59 (m, 1H), 3.53 (brs, 4H), 3.40 (s, 2H), 3.00 (s, 3H), 2.30 (brs, 4H), 1.63 (s, 6H), 1.24 (d, 6H, J=6.0 Hz)

Through the synthetic method according to Example 126, compounds from Example 127 to Example 141 were synthesized, and the data of each example are as follows.

TABLE 6 Ex. Compound Analysis data 127 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 739 (M + 1) isopropoxy-5-((4- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.45 (s, 1H), 9.88 pivaloylpiperazin-1- (brs, 1H), 8.21 (s, 1H), 7.93 (d, 1H, J = 8.7 Hz), 7.79 (s, yl)methyl)phenyl)propan-2- 1H), 7.70 (s, 1H), 7.47 (s, 1H), 7.27 (d, 1H, J = 8.7 Hz), yl)phenyl)-5- 6.94 (s, 1H), 6.57~6.60 (m, 3H), 4.48~4.51 (m, 1H), (methylsulfonamido)ben- 3.40 (brs, 4H), 3.33 (s, 2H), 2.92 (s, 3H), 2.22 (brs, 4H), zo[b]thiophene-2-carboxamide 1.55 (s, 6H), 1.17 (d, 6H, J = 6.0 Hz), 1.04 (s, 9H) 128 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 733 (M + 1) isopropoxy-5-((4- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.46 (s, 1H), 9.85 (methylsulfonyl)piperazin- (brs, 1H), 8.19 (s, 1H), 7.92 (d, 1H, J = 8.6 Hz), 7.79 (s, 1-yl)methyl)phenyl)propan- 1H), 7.69 (s, 1H), 7.48 (s, 1H), 7.27 (d, 1H, J = 8.9 Hz), 2-yl)phenyl)-5- 6.93 (s, 1H), 6.56~6.63 (m, 3H), 4.46~4.50 (m, 1H), (methylsulfonamido)ben- 3.39 (s, 2H), 3.00 (brs, 4H), 2.91 (s, 3H), 2.76 (s, 3H), zo[b]thiophene-2-carboxamide 2.35 (brs, 4H), 1.56 (s, 6H), 1.17 (d, 6H, J = 6.0 Hz) 129 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 765 (M + 1) isopropoxy-5-((4-(5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.86 isopropyl-1,2,4-oxadiazol-3- (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.85 (s, yl)piperazin-1- 1H), 7.79 (s, 1H), 7.56 (s, 1H), 7.36 (d, 1H, J = 8.7 Hz), yl)methyl)phenyl)propan-2- 7.00 (s, 1H), 6.70 (s, 2H), 6.63 (s, 1H), 4.56 (m, 1H), yl)phenyl)-5- 3.45 (s, 2H), 3.28 (brs, 4H), 3.05 (m, 1H), 3.01 (s, 3H), (methylsulfonamido)ben- 2.40 (brs, 4H), 1.62 (s, 6H), 1.21~1.25 (m, 12H) zo[b]thiophene-2-carboxamide 130 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 711 (M + 1) isopropoxy-5-((4-(oxetan-3- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.51 (s, 1H), 9.86 (s, yl)piperazin-1- 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.86 (s, 1H), yl)methyl)phenyl)propan-2- 7.79 (m, 1H), 7.51 (s, 1H), 7.36 (dd, 1H, J = 8.7, 1.6 Hz), yl)phenyl)-5- 7.02 (s, 1H), 6.64~6.66 (m, 3H), 4.55 (m, 1H), 4.40 (t, (methylsulfonamido)ben- 2H, J = 6.4 Hz), 4.31 (t, 2H, = 6.0 Hz), 3.39 (s, 2H), 3.28 zo[b]thiophene-2-carboxamide (m, 1H), 3.01 (s, 3H), 2.33 (brs, 4H), 2.18 (brs, 4H), 1.62 (s, 6H), 1.24 (d, 6H, J = 5.9 Hz) 131 N-(3-chloro-5-(2-(3-((4- LC/MS ESI (+): 762 (M + 1) (N,N-dimethylsulfamoyl)piperazin- ¹H-NMR(400 MHz, DMO-d₆): δ 10.53 (s, 1H), 9.86 1-yl)methyl)-5- (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.86 (s, isopropoxyphenyl)propan-2- 1H), 7.79 (s, 1H), 7.54 (s, 1H), 7.36 (d, 1H, J = 8.9 Hz), yl)phenyl)-5- 7.00 (s, 1H), 6.63~6.68 (m, 3H), 4.52~4.57 (m, 1H), (methylsulfonamido)ben- 3.43 (s, 2H), 3.10 (brs, 4H), 3.01 (s, 3H), 2.70 (s, 6H), zo[b]thiophene-2-carboxamide 2.36 (brs, 4H), 1.62 (s, 6H), 1.24 (d, 6H, J = 5.9 Hz) 132 N-(3-chloro-5-(2-(3-((1,1- LC/MS ESI (+): 704 (M + 1) dioxidothiomorpholino)methyl)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.86 (s, isopropoxyphenyl)propan-2- 1H), 8.28 (s, 1H), yl)phenyl)-5- 8.02 (d, 1H, J = 8.8 Hz), 7.84 (s, 1H), 7.79 (d, 1H, (methylsulfonamido)ben- J = 1.6 Hz), 7.55 (s, 1H), 7.36 (dd, 1H, J = 8.8, 2.0 Hz), zo[b]thiophene-2-carboxamide 7.01 (s, 1H), 6.73 (s, 2H), 6.62 (s, 1H), 4.51~4.61 (m, 1H), 3.60 (s, 2H), 3.07 (brs, 4H), 3.01 (s, 3H), 2.84 (brs, 4H), 1.63 (s, 6H), 1.23 (d, 6H, J = 2.0 Hz) 133 4-(3-(2-(3-chloro-5-(5- LC/MS ESI (+): 726 (M + 1) (methylsulfonamido)ben- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.85 zo[b]thiophene-2- (brs, 1H), 8.27 (s, 1H), 8.00 (d, 1H, J = 8.7 Hz), 7.85 (s, carboxamido)phenyl)pro- 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.35 (d, 1H, J = 8.8 Hz), pan-2-yl)-5-isopropoxybenzyl)- 7.00 (s, 1H), 6.62~6.68 (m, 3H), 4.53~4.57 (m, 1H), N,N-dimethylpiperazine-1- 3.37 (s, 2H), 3.04 (brs, 4H), 3.00 (s, 3H), 2.64 (s, 6H), carboxamide 2.29 (brs, 4H), 1.62 (s, 6H), 1.23 (d, 6H, J = 5.9 Hz) 134 N-(3-(2-(3-((2-oxa-7- LC/MS ESI (+): 696 (M + 1) azaspiro[3,5]nonan-7- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.86 yl)methyl)-5- (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.86 (s, isopropoxyphenyl)propan-2- 1H), 7.79 (s, 1H), 7.53 (s, 1H), 7.36 (d, 1H, J = 8.8 Hz), yl)-5-chlorophenyl)-5- 6.98 (s, 1H), 6.65 (s, 2H), 6.61 (s, 1H), 4.54 (m, 1H), (methylsulfonamido)ben- 4.20 (s, 4H), 3.45 (brs, 2H), 3.01 (s, 3H), 2.18 (brs, 4H), zo[b]thiophene-2-carboxamide 1.69 (brs, 4H), 1.61 (s, 6H), 1.23 (d, 6H, J = 5.9 Hz) 135 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 765 (M + 1) isopropoxy-5-((4-(5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.86 isopropyl-1,3,4-oxadiazol-2- (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.84(s, yl)piperazin-1- 1H), 7.80 (s, 1H), 7.55 (s, 1H), 7.35 (d, 1H, J = 8.6 Hz), yl)methyl)phenyl)propan-2- 7.01 (s, 1H), 6.64~6.70 (m, 3H), 4.53~4.59 (m, 1H), yl)phenyl)-5- 3.46 (s, 2H), 3.32 (brs, 4H), 3.00 (s, 3H), 2.90~2.97 (m, (methylsulfonamido)ben- 1H), 2.42 (brs, 4H), 1.63 (s, 6H), 1.24 (d, 6H, zo[b]thiophene-2-carboxamide J = 5.9 Hz), 1.18 (d, 6H, J = 6.9 Hz) 136 N-(3-fluoro-5-(2-(3- LC/MS ESI (+): 749 (M + 1) isopropoxy-5-((4-(5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.86 isopropyl-1,2,4-oxadiazol-3- (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.78 (d, yl)piperazin-1- 1H, J = 1.9 Hz), 7.63 (d, 1H, J = 11.1 Hz), 7.41 (s, 1H), yl)methyl)phenyl)propan-2- 7.35 (dd, 1H, J = 8.7, 2.1 Hz), 6.82 (d, 1H, J = 10.3 Hz), yl)phenyl)-5- 6.71 (s, 2H), 6.62 (s, 1H), 4.55 (m, 1H), 3.45 (s, 2H), (methylsulfonamido)ben- 3.27~3.29 (m, 4H), 3.05 (m, 1H), 3.01 (s, 3H), zo[b]thiophene-2-carboxamide 2.39~2.41 (m, 4H), 1.62 (s, 6H), 1.21~1.24 (m, 12H) 137 N-(3-fluoro-5-(2-(3- LC/MS ESI (+): 640 (M + 1) isopropoxy-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.86 (morpholinomethyl)phenyl)pro- (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.78 (s, pan-2-yl)phenyl)-5- 1H), 7.63 (d, 1H, J = 10.9 Hz), 7.34~7:38 (m, 2H), 6.82 (methylsulfonamido)ben- (d, 1H, J = 10.4 Hz), 6.61~6.82 (m, 3H), 4.51~4.57 (m, zo[b]thiophene-2-carboxamide 1H), 3.51 (brs, 4H), 3.38 (s, 2H), 3.01 (s, 3H), 2.30 (brs, 4H), 1.62 (s, 6H), 1.23 (d, 6H, J = 6.0 Hz) 138 N-(3-chloro-5-(2-(3-((1- LC/MS ESI (+): 709 (M + 1) methyl-1H-pyrazol-4- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.87 yl)methyl)-5-(1,1,2,2- (brs, 1H), 8.28 (s, 1H), 8.00 (d, 1H, J = 8.7 Hz), 7.90 (m, tetrafluoroethoxy)phenyl)pro- 1H), 7.78 (d, 1H, J = 2.0 Hz), 7.53 (m, 1H), 7.42 (s, 1H), pan-2-yl)phenyl)-5- 7.35 (dd, 1H, J = 8.7, 2.1 Hz), 7.23 (s, 1H), 7.15 (s, 1H), (methylsulfonamido)ben- 7.01 (m, 1H), 6.93 (s, 1H), 6.87 (s, 1H), 6.61~6.87 (m, zo[b]thiophene-2-carboxamide 1H), 3.78 (s, 2H), 3.75 (s, 3H), 2.99 (s, 3H), 1.64 (s, 6H) 139 N-(3-bromo-5-(2-(3-((4- LC/MS ESI (+): 864 (M + 1) (N,N-dimethylsulfamoyl)piperazin- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.87 (s, 1-yl)methyl)-5-(1,1,2,2- 1H), 8.28 (s, 1H), 8.02 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), tetrafluoroethoxy)phenyl)pro- 7.80 (s, 1H), 7.60 (s, 1H), 7.36 (d, 1H, J = 8.8 Hz), 7.15 pan-2-yl)phenyl)-5- (s, 1H), 7.13 (s, 1H), 7.09 (s, 1H), 7.02 (s, 1H), 6.78 (t, (methylsulfonamido)ben- 1H, J = 52.0 Hz), 3.54 (s, 2H), 3.11~3.18 (m, 4H), 3.05 zo[b]thiophene-2-carboxamide (s, 3H), 2.71 (s, 6H), 2.38~2.53 (m, 4H), 1.66 (s, 6H) 140 N-(3-fluoro-5-(2-(3- LC/MS ESI (+): 698 (M + 1) (morpholinomethyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.85 (1,1,2,2- (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.79 (s, tetrafluoroethoxy)phenyl)pro- 1H), 7.65 (d, 1H, J = 11.0 Hz), 7.40 (s, 1H), 7.36 (d, 1H, pan-2-yl)phenyl)-5- J = 10.4 Hz), 7.14 (s, 1H), 7.07 (s, 1H), 6.97 (s, 1H), 6.83 (methylsulfonamido)ben- (d, 1H, J = 10.4 Hz), 6.77 (t, 1H, J = 2.0 Hz), 3.53 (brs, zo[b]thiophene-2-carboxamide; 4H), 3.48 (s, 2H), 3.01 (s, 3H), 2.31 (brs, 4H), 1.66 (s, 6H) 141 N-(3-bromo-5-(2-(3-((4- LC/MS ESI (+): 813 (M + 1) (oxetan-3-yl)piperazin-1- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.50 (s, 1H), 9.87 (s, yl)methyl)-5-(1,1,2,2- 1H), 8.26 (s, 1H), 8.02 (s, 1H), 8.01 (d, 1H, J = 8.8 Hz), tetrafluoroethoxy)phenyl)pro- 7.78 (s, 1H), 7.57 (s, 1H), 7.35 (d, 1H, J = 8.4 Hz), 7.16 pan-2-yl)phenyl)-5- (s, 1H), 7.09 (s, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 6.77 (t, (methylsulfonamido)ben- 1H, J = 52.0 Hz), 4.40 (t, 2H, J = 6.0 Hz), 4.32 (t, 2H, zo[b]thiophene-2-carboxamide J = 6.0 Hz), 3.48 (s, 2H), 3.26~3.28 (m, 1H), 3.00 (s, 3H) 2.34 (s, 4H) 2.18 (s, 4H), 1.65 (s, 6H)

Example 142 Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(1-methyl-1H-pyrazol-5-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 5-(3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-isopropoxyphenyl)-1-methyl-1H-pyrazole

The synthesis procedure of Intermediate 44 was repeated except for using 1-bromo-3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-isopropoxybenzene (50.0 mg, 0.12 mmol) to obtain 5-(3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-isopropoxyphenyl)-1-methyl-1H-pyrazole (32.0 mg, 64%).

LC/MS ESI (+): 414 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.07 (s, 1H), 8.03 (s, 1H), 7.54 (s, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 6.27 (s, 1H), 4.53-4.56 (m, 1H), 3.83 (s, 3H), 1.73 (s, 6H), 1.34 (d, 6H, J=6.0 Hz)

(b) Synthesis of 3-chloro-5-(2-(3-isopropoxy-5-(1-methyl-1H-pyrazol-5-yl)phenyl)propan-2-yl)aniline

The synthesis procedure of Intermediate 40 was repeated except for using 5-(3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-5-isopropoxyphenyl)-1-methyl-1H-pyrazole (32.0 mg, 0.08 mmol) to obtain 3-chloro-5-(2-(3-isopropoxy-5-(1-methyl-1H-pyrazol-5-yl)phenyl)propan-2-yl)aniline (22.0 mg, 76%).

LC/MS ESI (+): 384 (M+1)

(c) Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(1-methyl-1H-pyrazol-5-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-chloro-5-(2-(3-isopropoxy-5-(1-methyl-1H-pyrazol-5-yl)phenyl)propan-2-yl)aniline (16.0 mg, 0.06 mmol) to obtain N-(3-chloro-5-(2-(3-isopropoxy-5-(1-methyl-1H-pyrazol-5-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (15.0 mg, 42%).

LC/MS ESI (+): 637 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 9.88 (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J=8.7 Hz), 7.89 (s, 1H), 7.79 (s, 1H), 7.58 (s, 1H), 7.44 (s, 1H), 7.35 (d, 1H, J=8.7 Hz), 7.10 (s, 1H), 6.88 (s, 2H), 6.75 (s, 1H), 6.39 (s, 1H), 4.63-4.69 (m, 1H), 3.80 (s, 3H), 3.01 (s, 3H), 1.68 (s, 6H), 1.25 (d, 6H, J=6.0 Hz)

Through the synthetic method according to Example 142, compounds from Example 143 to Example 147 were synthesized, and the data of each example are as follows.

TABLE 7 Ex. Compound Analysis data 143 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 637 (M + 1) isopropoxy-5-(1-methyl- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 9.88 1H-pyrazol-4- (brs, 1H), 8.28 (s, 1H), 8.13 (s, 1H), 8.01 (d, 1H, yl)phenyl)propan-2- J = 8.7 Hz), 7.89 (s, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.54 yl)phenyl)-5- (s, 1H), 7.35 (d, 1H, J = 8.7 Hz), 7.05 (s, 1H), 7.11 (s, (methylsulfonamido)ben- 1H), 6.95 (s, 1H), 6.47 (s, 1H), 4.60~4.66 (m, 1H), 3.83 zo[b]thiophene-2-carboxamide (s, 3H), 3.01 (s, 3H), 1.66 (s, 6H), 1.23 (d, 6H, J = 6.0 Hz) 144 N-(3-chloro-5-(2-(3-(3- LC/MS ESI (+): 671 (M + 1) hydroxy-4-methylpiperazin- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.58 (s, 1H), 8.28 (s, 1-yl)-5- 1H), 7.98 (d, 1H, J = 8.8 Hz), 7.86 (s, 1H), 7.76 (s, 1H), isopropoxyphenyl)propan- 7.54 (s, 1H), 7.34 (dd, 1H, J = 8.8, 1.6 Hz), 7.00 (s, 1H), 2-yl)phenyl)-5- 6.43 (s, 1H), 6.34 (s, 1H), 6.16 (s, 1H), 4.48~4.60 (m, (methylsulfonamido)ben- 1H), 3.40~3.46 (m, 5H), 3.13 (s, 3H), 2.99~3.05 (m, zo[b]thiophene-2-carboxamide 2H), 3.00 (s, 3H), 1.61 (s, 6H), 1.20 (d, 6H, J = 6.0 Hz) 145 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 642 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.86 morpholinophenyl)propan- (brs, 1H), 8.23 (s, 1H), 7.98 (d, 1H, J = 8.9 Hz), 7.82 (s, 2-yl)phenyl)-5- 1H), 7.72 (s, 1H), 7.40 (s, 1H), 7.29 (d, 1H, J = 8.7 Hz), (methylsulfonamido)ben- 6.94 (s, 1H), 6.33 (s, 1H), 6.22 (s, 1H), 6.07 (s, 1H), zo[b]thiophene-2-carboxamide 4.46~4.48 (m, 1H), 3.62(brs, 4H), 2.98 (s, 3H), 2.94 (brs, 4H), 1.54 (s, 6H), 1.17 (d, 6H, J = 6.0 Hz) 146 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 626 (M + 1) isopropoxy-5-(pyrrolidin-1- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.90 (s, yl)phenyl)propan-2- 1H), 8.31 (s, 1H), yl)phenyl)-5- 8.04 (d, 1H, J = 8.8 Hz), 7.89 (s, 1H), 7.80 (s, 1H), 7.54 (methylsulfonamido)ben- (s, 1H), 7.37 (dd, 1H, J = 8.8, 2.0 Hz), 7.02 (s, 1H), 5.98 zo[b]thiophene-2-carboxamide (s, 1H), 5.95 (s, 1H), 5.89 (s, 1H), 4.48~4.54 (m, 1H), 3.15~3.18 (m, 4H), 3.03 (s, 3H), 1.90~1.93 (m, 4H), 1.61 (s, 6H), 1.21 (d, 6H, J = 6.0 Hz) 147 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 655 (M + 1) isopropoxy-5-(4- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.45 (s, 1H), 9.81 methylpiperazin-1- (brs, 1H), 8.22 (s, 1H), 7.95 (d, 1H, J = 8.8 Hz), 7.81 (s, yl)phenyl)propan-2- 1H), 7.73 (s, 1H), 7.45 (s, 1H), 7.29 (dd, 1H, J = 8.8, yl)phenyl)-5- 2.2 Hz), 6.94 (s, 1H), 6.32 (s, 1H), 6.20 (s, 1H), 6.04 (s, (methylsulfonamido)ben- 1H), 4.44~4.46 (m, 1H), 2.99~3.00 (m, 4H), 2.94 (s, zo[b]thiophene-2-carboxamide 3H), 2.30~2.35 (m, 4H), 2.13 (s, 3H), 1.53 (s, 6H), 1.13 (d, 6H, J = 6.0 Hz)

Example 148 Synthesis of N-(6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 2,6-dichloro-N-methoxy-N-methylisonicotinamide

2,6-Dichloroisonicotinic acid (192.0 mg, 1.00 mmol) was dissolved in anhydrous CH₂Cl₂ (10.0 mL), and (COCl)₂ (130.0 μL, 1.50 mmol) and a catalytic amount of anhydrous DMF were added. The mixture was stirred at 0° C. for 1 hour and dried for 1 hour under reduced pressure. The residue was dissolved in anhydrous CH₂Cl₂ (10.0 mL), and N,O-dimethylhydroxylamine (292.0 mg, 3.00 mmol) and pyridine (480.0 μL, 6.00 mmol) were added at 0° C. The reaction mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=1:4) to obtain 2,6-dichloro-N-methoxy-N-methylisonicotinamide (220.0 mg, 94%) as a white solid.

LC/MS ESI (+): 235 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.50 (s, 2H), 3.58 (s, 3H), 3.38 (s, 3H)

(b) Synthesis of (2,6-dichloropyridin-4-yl)(3-methoxy-5-(trifluoromethoxy)phenyl)methanone

1-Bromo-3-methoxy-5-(trifluoromethoxy)benzene (5.0 g, 18.72 mmol) was dissolved in THF (70.0 mL), and tert-BuLi (11.9 mL, 20.16 mmol) was slowly added at −78° C., followed by stirring for 2 hours. 2,6-Dichloro-N-methoxy-N-methylisonicotinamide (3.4 g, 14.40 mmol) was dissolved in THF (7.6 mL) and added to the reaction mixture, followed by stirring at 0° C. for 2 hours. The reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:CH₂Cl₂=1:10) to obtain (2,6-dichloropyridin-4-yl)(3-methoxy-5-(trifluoromethoxy)phenyl)methanone (2.8 g, 55%) as a yellow solid.

LC/MS ESI (+): 366 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.53 (s, 2H) 7.24 (s, 1H), 7.19 (s, 1H), 7.06 (s, 1H), 3.89 (s, 3H)

(c) Synthesis of 2,6-dichloro-4-(dichloro(3-methoxy-5-(trifluoromethoxy)phenyl)methyl)pyridine

The synthesis procedure of Intermediate 37 was repeated except for using (2,6-dichloropyridin-4-yl)(3-methoxy-5-(trifluoromethoxy)phenyl)methanone (2.8 g, 7.64 mmol) to obtain 2,6-dichloro-4-(dichloro(3-methoxy-5-(trifluoromethoxy)phenyl)methyl)pyridine (1.9 g, 60%).

LC/MS ESI (+): 420 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.45 (s, 2H) 7.05 (s, 1H), 7.03 (s, 1H), 6.82 (s, 1H), 3.85 (s, 3H)

(d) Synthesis of 2,6-di chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridine

In CH₂Cl₂ (30.0 mL), 1.0 M solution of TiCl₄ in CH₂Cl₂ (9.0 mL, 9.00 mmol) and 1.2 M solution of dimethylzinc in toluene (22.6 mL, 27.06 mmol) were added at −40° C., followed by stirring for 30 minutes. A solution of 2,6-dichloro-4-(dichloro(3-methoxy-5-(trifluoromethoxy)phenyl)methyl)pyridine (1.9 g, 5.0 mmol) in CH₂Cl₂ (15.0 mL) was slowly added at −40° C., and the reaction mixture was heated to room temperature, followed by stirring for 12 hours. Water was added to quench the reaction, and then extracted with CH₂Cl₂. The organic extract was dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=1:1) to obtain 2,6-dichloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridine (540.0 mg, 31%) as an off-white oil.

LC/MS ESI (+): 380 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.07 (s, 2H) 6.66 (s, 1H), 6.62 (s, 2H), 3.79 (s, 3H), 1.64 (s, 6H)

(e-I) Synthesis of 6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-amine (method I)

In 2,6-dichloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridine (70.0 mg, 0.18 mmol), 35% solution of NH₄OH in H₂O (3.0 mL) and 1,4-dioxane (1.0 mL) were added. The mixture was stirred at 160° C. for 12 hours, and then, cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=1:9) to obtain 6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-amine (40.0 mg, 60%) as an off-white oil.

LC/MS ESI (+): 361 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 6.66 (s, 2H), 6.63 (s, 1H), 6.50 (s, 1H), 6.18 (s, 1H), 4.48 (brs, 2H), 3.78 (s, 3H), 1.58 (s, 6H)

(e-II) Synthesis of 6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-amine (method II)

2,6-Dichloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridine (50.0 mg, 0.13 mmol), NaN₃ (17.0 mg, 0.26 mmol), Cu₂O (18.7 mg, 0.13 mmol), and L-proline (19.5 mg, 0.17 mmol) were dissolved in DMSO (1.0 mL), followed by stirring at 100° C. for 12 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=9:1) to obtain 6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-amine (18.0 mg, 38%) as an off-white oil.

(f) Synthesis of N-(6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-nitrobenzo[b]thiophene-2-carboxamide

5-Nitrobenzo[b]thiophene-2-carboxylic acid (13.3 mg, 0.06 mmol) was dissolved in anhydrous CH₂Cl₂ (1.0 mL), and (COCl)₂ (5.3 μL, 0.06 mmol) and a catalytic amount of anhydrous DMF were added. The mixture was stirred at 0° C. for 1 hour and dried for 1 hour under reduced pressure. The residue was dissolved in anhydrous pyridine (1.0 mL), and, 6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-amine (10.0 mg, 0.03 mmol) was added at 0° C. The reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=1:4) to obtain N-(6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-nitrobenzo[b]thiophene-2-carboxamide (11.0 mg, 72%) as a yellow solid.

LC/MS ESI (+): 566 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.81 (d, 1H, J=2.0 Hz), 8.55 (s, 1H), 8.33 (dd, 1H, J=8.8, 2.0 Hz), 8.27 (d, 1H, J=1.2 Hz), 8.04 (d, 1H, J=8.8 Hz), 8.03 (s, 1H), 6.90 (d, 1H, J=1.2 Hz), 6.69 (t, 1H, J=2.0 Hz), 6.67 (s, 1H), 6.05 (s, 1H), 3.79 (s, 3H), 1.70 (s, 6H)

(g) Synthesis of 5-amino-N-(6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Intermediate 40 was repeated except for using N-(6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-nitrobenzo[b]thiophene-2-carboxamide (10.0 mg, 0.02 mmol) to obtain 5-amino-N-(6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)benzo[b]thiophene-2-carboxamide (9.0 mg, 91%).

LC/MS ESI (+): 536 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.46 (s, 1H), 8.31 (d, 1H, J=1.2 Hz), 7.72 (s, 1H), 7.65 (d, 1H, J=8.8 Hz), 7.13 (d, 1H, J=2.0 Hz), 6.91 (dd, 1H, J=8.8, 2.0 Hz), 6.83 (d, 1H, J=1.6 Hz), 6.66-6.68 (m, 2H), 6.63-6.64 (m, 1H), 3.80-3.82 (m, 2H), 3.78 (s, 3H), 1.69 (s, 6H)

(h) Synthesis of N-(6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Intermediate 6-a was repeated except for using 5-amino-N-(6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)benzo[b]thiophene-2-carboxamide (9.0 mg, 0.02 mmol) to obtain N-(6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (1.7 mg, 17%).

LC/MS ESI (+): 614 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.42 (s, 1H), 9.88 (s, 1H), 8.50 (s, 1H), 8.10 (s, 1H), 7.98 (d, 1H, J=8.4 Hz), 7.70 (s, 1H), 7.32 (d, 1H, J=8.4 Hz), 7.12 (s, 1H), 6.85 (s, 2H), 6.78 (s, 1H), 3.78 (s, 3H), 2.97 (s, 3H), 1.66 (s, 6H)

Example 149 Synthesis of N-(2-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 148 was repeated except for using 4,6-dichloropicolinic acid (3.0 g, 15.63 mmol) to obtain N-(2-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (49.6 mg).

LC/MS ESI (+): 614 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.86 (s, 1H), 9.96 (s, 1H), 8.31 (s, 1H), 8.02 (d, 1H, J=8.8 Hz), 7.88 (s, 1H), 7.80 (s, 1H), 7.54 (s, 1H), 7.36 (d, 1H, J=8.8 Hz), 6.82 (s, 2H), 6.75 (s, 1H), 3.77 (s, 3H), 3.00 (s, 3H), 1.66 (s, 6H)

Example 150 Synthesis of N-(4-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 148 was repeated except for using 4,6-dichloropicolinic acid (3.0 g, 15.63 mmol) to obtain N-(4-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (5.7 mg).

LC/MS ESI (+): 614 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.05 (s, 1H), 9.91 (s, 1H), 8.57 (s, 1H), 8.09 (d, 1H, J=1.6 Hz), 8.03 (d, 1H, J=8.8 Hz), 7.78 (s, 1H), 7.37 (dd, 1H, J=8.8, 1.6 Hz), 7.19 (d, 1H, J=1.6 Hz), 6.86 (t, 1H, J=2.0 Hz), 6.80 (s, 2H), 3.77 (s, 3H), 3.02 (s, 3H), 1.75 (s, 6H)

Example 151 Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-2-(methylsulfonamido)thieno[2,3-b]pyrazine-6-carboxamide (a) Synthesis of methyl 5-chloro-4-nitrothiophene-2-carboxylate

5-Chloro-4-nitrothiophene-2-carboxylic acid (1.0 g, 4.82 mmol) was dissolved in MeOH (50.0 mL), and SOCl₂ (699.0 μL, 9.63 mmol) was slowly added. After refluxing for 20 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain methyl 5-chloro-4-nitrothiophene-2-carboxylate (797.5 mg, 75%) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ 8.18 (s, 1H), 3.94 (s, 3H)

(b) Synthesis of methyl 5-((2-ethoxy-2-oxoethyl)amino)-4-nitrothiophene-2-carboxylate

Methyl 5-chloro-4-nitrothiophene-2-carboxylate (697.5 mg, 3.15 mmol) was dissolved in anhydrous CH₃CN (31.0 mL), and H-Gly-OEt.HCl (483.2 mg, 3.46 mmol) and K₂CO₃ (1.1 g, 7.87 mmol) were added at room temperature. The mixture was refluxed at 70° C. for 3 hours and then cooled to room temperature. The reaction mixture was poured into ice water. The resulting solid was filtered to obtain methyl 5-((2-ethoxy-2-oxoethyl)amino)-4-nitrothiophene-2-carboxylate (713.2 mg, 79%) as a yellow solid.

LC/MS ESI (+): 289 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.74 (s, 1H), 8.04 (s, 1H), 4.33 (q, 2H, J=7.1 Hz), 4.10 (d, 2H, J=5.4 Hz), 3.87 (s, 3H), 1.34 (t, 3H, J=7.1 Hz)

(c) Synthesis of methyl 2-oxo-1,2,3,4-tetrahydrothieno[2,3-b]pyrazine-6-carboxylate

Methyl 5-((2-ethoxy-2-oxoethyl)amino)-4-nitrothiophene-2-carboxylate (713.2 mg, 2.47 mmol) was dissolved in a mixture of AcOH/H₂O (14.3 mL, 20/3 v/v), and Fe (414.4 mg, 7.42 mmol) was added at room temperature. The mixture was refluxed at 70° C. for 24 hours and then cooled to room temperature. The reaction mixture was poured into ice water, and the resulting solid was filtered to obtain methyl 2-oxo-1,2,3,4-tetrahydrothieno[2,3-b]pyrazine-6-carboxylate (415.0 mg, 79%) as a green solid.

LC/MS ESI (+): 213 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.26 (s, 1H), 7.20 (s, 1H), 7.06 (s, 1H), 3.87-3.89 (m, 2H), 3.69 (s, 3H)

(d) Synthesis of methyl 2-oxo-1,2-dihydrothieno[2,3-b]pyrazine-6-carboxylate

Methyl 2-oxo-1,2,3,4-tetrahydrothieno[2,3-b]pyrazine-6-carboxylate (415.0 mg, 1.96 mmol) was dissolved in anhydrous THF (20.0 mL), and MnO₂ (849.8 mg, 9.78 mmol) was added at room temperature, followed by stirring for 10 days. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain methyl 2-oxo-1,2-dihydrothieno[2,3-b]pyrazine-6-carboxylate (220.5 mg, 54%) as a brown solid.

LC/MS ESI (+): 211 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 12.76 (brs, 1H), 8.13 (brs, 1H), 7.62 (brs, 1H), 3.89 (s, 3H)

(e) Synthesis of methyl 2-chlorothieno[2,3-b]pyrazine-6-carboxylate

A mixture of methyl 2-oxo-1,2-dihydrothieno[2,3-b]pyrazine-6-carboxylate (220.5 mg, 1.05 mmol) and POCl₃ (5.9 mL, 62.94 mmol) was refluxed at 110° C. for 15 hours, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, washed with sat. NaHCO₃ aqueous solution and brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure to obtain methyl 2-chlorothieno[2,3-b]pyrazine-6-carboxylate (205.2 mg, 86%) as a brown solid.

LC/MS ESI (+): 229 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.61 (s, 1H), 8.10 (s, 1H), 4.01 (s, 3H)

(f) Synthesis of 2-chlorothieno[2,3-b]pyrazine-6-carboxylic acid

Methyl 2-chlorothieno[2,3-b]pyrazine-6-carboxylate (298.0 mg, 1.30 mmol) was dissolved in a mixture of THF/EtOH (10.0 mL, 1/1 v/v), and 2.0 N NaOH aqueous solution (3.26 mL, 6.52 mmol) was added at room temperature, followed by stirring at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in water. 1 N HCl aqueous solution was added for acidification to pH 1-2. The resulting solid precipitate was filtered and dried under reduced pressure to obtain 2-chlorothieno[2,3-b]pyrazine-6-carboxylic acid (179.8 mg, 64%) as a brown solid.

LC/MS ESI (+): 215 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 8.89 (s, 1H), 8.14 (s, 1H)

(g) Synthesis of 2-chloro-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)thieno[2,3-b]pyrazine-6-carboxamide

The synthesis procedure of Example 1 was repeated except for using 2-chlorothieno[2,3-b]pyrazine-6-carboxylic acid (179.8 mg, 0.84 mmol) to obtain 2-chloro-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)thieno[2,3-b]pyrazine-6-carboxamide (295.4 mg, 60%) as a yellow solid.

LC/MS ESI (+): 584 (M+1)

¹H-NMR (400 MHz, CDCl₃): 0.3-8.60 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.75 (m, 1H), 7.22 (m, 1H), 7.07 (m, 1H), 6.64-6.66 (m, 2H), 6.59 (m, 1H), 4.48 (m, 1H), 1.66 (s, 6H), 1.32 (d, 6H, J=6.0 Hz)

(h) Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-2-((4-methoxybenzyl)amino)thieno[2,3-b]pyrazine-6-carboxamide

To a solution of 2-chloro-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)thieno[2,3-b]pyrazine-6-carboxamide (295.4 mg, 0.51 mmol) in anhydrous 1,4-dioxane (10.0 mL), (4-methoxyphenyl)methaneamine (99.0 μL, 0.76 mmol), Pd(OAc)₂ (11.3 mg, 0.05 mmol), Xantphos (40.9 mg, 0.07 mmol) and Cs₂CO₃ (493.6 mg, 1.52 mmol) were added. The mixture was reacted in a microwave with 100 W, at 120° C. for 30 minutes and cooled to room temperature. Water was added, followed by extracting with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-2-((4-methoxybenzyl)amino)thieno[2,3-b]pyrazine-6-carboxamide (112.5 mg, 33%) as a yellow solid.

LC/MS ESI (+): 685 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.95 (s, 1H), 7.72-7.74 (m, 3H), 7.32 (d, 2H, J=8.3 Hz), 7.21 (s, 1H), 7.02 (s, 1H), 6.90 (d, 2H, J=8.1 Hz), 6.65 (s, 2H), 6.59 (s, 1H), 4.99 (m, 1H), 4.58 (d, 2H, J=5.4 Hz), 4.48 (m, 1H), 3.81 (s, 3H), 1.65 (s, 6H), 1.32 (d, 6H, J=6.0 Hz)

(i) Synthesis of 2-amino-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)thieno[2,3-b]pyrazine-6-carboxamide

N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-2-((4-methoxybenzyl)amino)thieno[2,3-b]pyrazine-6-carboxamide (112.5 mg, 0.16 mmol) was dissolved in anhydrous CH₂Cl₂ (3.2 mL), and TFA (1.6 mL) was added at room temperature. The mixture was stirred at 40° C. for 19 hours and then concentrated under reduced pressure. The residue was basified with sat. NaHCO₃ aqueous solution (pH 9) and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:2) to obtain 2-amino-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)thieno[2,3-b]pyrazine-6-carboxamide (80.0 mg, 86%) as a yellow solid.

LC/MS ESI (+): 565 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.06 (s, 1H), 7.72-7.73 (m, 2H), 7.67 (s, 1H), 7.23 (s, 1H), 7.03 (s, 1H), 7.65 (s, 2H), 6.59 (s, 1H), 4.75 (s, 2H), 4.47 (m, 1H), 1.66 (s, 6H), 1.32 (d, 6H, J=6.0 Hz)

(j) Synthesis of 2-[bis(methylsulfonyl)amino]-N-[3-chloro-5-[1-[3-isopropoxy-5-(trifluoromethoxy)phenyl]-1-methyl-ethyl]phenyl]thieno[2,3-b]pyrazine-6-carboxamide

2-Amino-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)thieno[2,3-b]pyrazine-6-carboxamide (20.0 mg, 0.04 mmol) was dissolved in anhydrous CH₂Cl₂ (0.7 mL), and DIPEA (12.3 μL, 0.07 mmol) and methanesulfonyl chloride (4.1 μL, 0.05 mmol) were added at room temperature. The mixture was stirred at room temperature for 16 hours, and water was added, followed by extracting with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain 2-[bis(methylsulfonyl)amino]-N-[3-chloro-5-[1-[3-isopropoxy-5-(trifluoromethoxy)phenyl]-1-methyl-ethyl]phenyl]thieno[2,3-b]pyrazine-6-carboxamide (9.2 mg, 36%) as a yellow solid.

LC/MS ESI (+): 721 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.61 (s, 1H), 7.94 (s, 1H), 7.92 (s, 1H), 7.73 (s, 1H), 7.21 (s, 1H), 7.06 (s, 1H), 6.64-6.65 (m, 2H), 6.59 (s, 1H), 4.48 (m, 1H), 3.64 (s, 6H), 1.65 (s, 6H), 1.32 (d, 6H, J=6.0 Hz)

(k) Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-2-(methylsulfonamido)thieno[2,3-b]pyrazine-6-carboxamide

N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-2-(N-(methylsulfonyl)methylsulfonamido)thieno[2,3-b]pyrazine-6-carboxamide (9.2 mg, 0.01 mmol) was dissolved in THF (0.2 mL), and 1.0 N KOH aqueous solution (38.2 μL, 0.04 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours, and water was added, followed by extracting with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:2) to obtain N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-2-(methylsulfonamido)thieno[2,3-b]pyrazine-6-carboxamide (4.0 mg, 50%) as a white solid.

LC/MS ESI (+): 643 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.40 (s, 1H), 10.64 (s, 1H), 8.41 (s, 1H), 8.32 (s, 1H), 7.91 (s, 1H), 7.55 (s, 1H), 7.08 (s, 1H), 6.77 (s, 1H), 6.73 (s, 1H), 6.71 (s, 1H), 4.63 (m, 1H), 3.39 (s, 3H), 1.64 (s, 6H), 1.23 (d, 6H, J=5.5 Hz)

Example 152 Synthesis of N-(3-(2-(4-bromophenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 1-(2-(4-bromophenyl)propan-2-yl)-3-chloro-5-nitrobenzene

1-(2-Bromopropan-2-yl)-3-chloro-5-nitrobenzene (Example 166-b) (200.0 mg, 0.72 mmol) and bromobenzene (1.1 mL, 10.77 mmol) were dissolved in 1,2-dichloroethane (7.0 mL), and AlCl₃ (287.2 mg, 2.15 mmol) was added at room temperature. The mixture was stirred at room temperature for 12 hours, and water was added, followed by extracting with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 1-(2-(4-bromophenyl)propan-2-yl)-3-chloro-5-nitrobenzene (255.4 mg, 100%) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃): δ 8.06 (s, 1H), 8.00 (s, 1H), 7.46 (s, 1H), 7.44 (d, 2H, J=8.6 Hz), 7.07 (d, 2H, J=8.6 Hz), 1.70 (s, 6H)

(b) Synthesis of 3-(2-(4-bromophenyl)propan-2-yl)-5-chloroaniline

The synthesis procedure of Intermediate 40 was repeated except for using 1-(2-(4-Bromophenyl)propan-2-yl)-3-chloro-5-nitrobenzene (84.2 mg, 0.24 mmol) to obtain 3-(2-(4-bromophenyl)propan-2-yl)-5-chloroaniline (67.1 mg, 87%).

LC/MS ESI (+): 324 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.38 (d, 1H, J=8.6 Hz), 7.09 (d, 1H, J=8.6 Hz), 6.60 (m, 1H), 6.51 (m, 1H), 6.32 (m, 1H), 3.65 (s, 2H), 1.59 (s, 6H)

(c) Synthesis of N-(3-(2-(4-bromophenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-(2-(4-bromophenyl)propan-2-yl)-5-chloroaniline (67.1 mg, 0.21 mmol) to obtain N-(3-(2-(4-bromophenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (40.4 mg, 34%).

LC/MS ESI (+): 577 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.87 (s, 1H), 8.27 (s, 1H), 8.02 (d, 1H, J=8.7 Hz), 7.89 (s, 1H), 7.79 (s, 1H), 7.49-7.51 (m, 3H), 7.36 (d, 1H, J=8.7 Hz), 7.21 (d, 2H, J=8.0 Hz), 7.03 (s, 1H), 3.01 (s, 3H), 1.64 (s, 6H)

Through the synthetic method according to Example 152, compounds from Example 153 to Example 163 were synthesized, and the data of each example are as follows.

TABLE 8 Ex. Compound Analysis data 153 N-(3-chloro-5-(2-(3,4- LC/MS ESI (+): 559 (M + 1) dimethoxyphenyl)propan- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.89 (s, 2-yl)phenyl)-5- 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 9.0 Hz), 7.87 (s, 1H), (methylsulfonamido)ben- 7.78 (s, 1H), 7.51 (s, 1H), 7.36 (d, 1H, J = 9.0 Hz), 7.00 (s, zo[b]thiophene-2-carboxamide 1H), 6.76~6.87 (m, 3H), 3.72 (s, 3H), 3.69 (s, 3H), 3.01 (s, 3H), 1.63 (s, 6H) 154 N-(3-chloro-5-(2-(2,4- LC/MS ESI (+): 559 (M + 1) dimethoxyphenyl)propan- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.50 (s, 1H), 9.88 (s, 2-yl)phenyl)-5- 1H), 8.29 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.81 (s, 1H), (methylsulfonamido)ben- 7.78 (s, 1H), 7.39 (s, 1H), 7.33~7.36 (m, 2H), 6.85 (t, zo[b]thiophene-2-carboxamide 1H, J = 1.7 Hz), 6.55 (dd, 1H, J = 8.6, 2.5 Hz), 6.49 (d, 1H, J = 2.5 Hz), 3.75 (s, 3H), 3.40 (s, 3H), 3.01 (s, 3H), 1.58 (s, 6H) 155 N-(3-chloro-5-(2-(4- LC/MS ESI (+): 529 (M + 1) methoxyphenyl)propan-2- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.87 (s, yl)phenyl)-5- 1H), 8.29 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.86 (s, 1H), (methylsulfonamido)ben- 7.78 (s, 1H), 7.51 (s, 1H), 7.35 (d, 1H, J = 8.7 Hz), 7.16 zo[b]thiophene-2-carboxamide (d, 2H, J = 8.8 Hz), 6.99 (s, 1H), 6.87 (d, 2H, J = 8.8 Hz), 3.72 (s, 3H), 3.01 (s, 3H), 1.62 (s, 6H) 156 N-(3-chloro-5-(2-(2,5- LC/MS ESI (+): 559 (M + 1) dimethoxyphenyl)propan- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.51 (s, 1H), 9.89 (s, 2-yl)phenyl)-5- 1H), 8.30 (s, 1H), 8.03 (d, 1H, J = 8.7 Hz), 7.85 (s, 1H), (methylsulfonamido)ben- 7.80 (s, 1H), 7.39 (s, 1H), 7.36 (d, 1H, J = 8.7 Hz), 7.00 (s, zo[b]thiophene-2-carboxamide 1H), 6.84~6.90 (m, 3H), 3.77 (s, 3H), 3.31 (s, 3H), 3.02 (s, 3H), 1.61 (s, 6H) 157 N-(3-chloro-5-(2-(4- LC/MS ESI (+): 545 (M + 1) (methylthio)phenyl)propan- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.87 (s, 2-yl)phenyl)-5- 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.88 (s, 1H), (methylsulfonamido)ben- 7.79 (s, 1H), 7.51 (s, 1H), 7.36 (d, 1H, J = 8.6 Hz), zo[b]thiophene-2-carboxamide 7.17~7.22 (m, 4H), 7.00 (s, 1H), 3.01 (s, 3H), 2.45 (s, 3H), 1.63 (s, 6H) 158 W-(3-chloro-5-(2-(4- LC/MS ESI (+): 533 (M + 1) chlorophenyl)propan-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.87 (s, yl)phenyl)-5- 1H), 8.27 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.88 (s, 1H), (methylsulfonamido)ben- 7.79 (s, 1H), 7.49 (s, 1H), 7.34~7.38 (m, 3H), 7.27 (d, zo[b]thiophene-2-carboxamide 2H, J = 8.0 Hz), 7.03 (s, 1H), 3.01 (s, 3H), 1.64 (s, 6H) 159 N-(3-chloro-5-(2-(4-(1- LC/MS ESI (+): 579 (M + 1) methyl-1H-pyrazol-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.88 yl)phenyl)propan-2- (brs, 1H), 8.29 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.90 (s, yl)phenyl)-5- 1H), 7.79 (d, 1H, J = 1.6 Hz), 7.58 (s, 1H), 7.49 (d, 2H, (methylsulfonamido)ben- J = 8.3 Hz), 7.48 (s, 1H), 7.34~7.38 (m, 3H), 7.08 (s, 1H), zo[b]thiophene-2-carboxamide 6.39 (d, 1H, J = 1.7 Hz), 3.85 (s, 3H), 3.01 (s, 3H), 1.70 (s, 6H) 160 N-(3-chloro-5-(2-(4- LC/MS ESI (+): 561 (M + 1) (methylsulfinyl)phenyl)propan- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.87 (s, 2-yl)phenyl)-5- 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.90 (s, 1H), (methylsulfonamido)ben- 7.78 (s, 1H), 7.64 (d, 2H, J = 8.0 Hz), 7.55 (s, 1H), 7.47 zo[b]thiophene-2-carboxamide (d, 2H, J = 8.0 Hz), 7.36 (d, 1H, J = 8.7 Hz), 7.06 (s, 1H), 3.02 (s, 3H), 2.75 (s, 3H), 1.70 (s, 6H) 161 N-(3-chloro-5-(2-(4- LC/MS ESI (+): 577 (M + 1) (methylsulfonyl)phenyl)propan- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 9.87 2-yl)phenyl)-5- (brs, 1H), 8.27 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.91 (s, (methylsulfonamido)ben- 1H), 7.87 (d, 2H, J = 7.9 Hz), 7.78 (s, 1H), 7.51~7.54 (m, zo[b]thiophene-2-carboxamide 3H), 7.35 (d, 1H, J = 8.8 Hz), 7.06 (s, 1H), 3.20 (s, 3H), 3.00 (s, 3H), 1.69 (s, 6H) 162 N-(3-chloro-5-(2-(3,4- LC/MS ESI (+): 535 (M + 1) difluorophenyl)propan-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.88 (s, yl)phenyl)-5- 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.89 (s, 1H), (methylsulfonamido)ben- 7.80 (s, 1H), 7.48 (s, 1H), 7.34~7.37 (m, 3H), 7.05~7.06 zo[b]thiophene-2-carboxamide (m, 2H), 3.01 (s, 3H), 1.65 (s, 6H) 163 N-(3-chloro-5-(2-(4- LC/MS ESI (+): 565 (M + 1) chlorophenyl)propan-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.66 (s, 1H), 8.30 (s, yl)phenyl)-6-fluoro-5-(N- 1H), 8.18 (d, 1H, J = 7.4 Hz), 8.14 (d, 1H, J = 10.5 Hz), 7.87 methylmethylsulfonamido) (s, 1H), 7.49 (s, 1H), 7.37 (d, 2H, J = 8.7 Hz), 7.27 (d, 2H, benzo[b]thiophene-2- J = 8.7 Hz), 7.04 (s, 1H), 3.28 (s, 3H), 3.12 (s, 3H), 1.64 carboxamide (s, 6H)

Example 164 Synthesis of N-(3-chloro-5-(2-(piperidin-1-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 1-(2-(3-chloro-5-nitrophenyl)propan-2-yl)piperidine

1-(2-Bromopropan-2-yl)-3-chloro-5-nitrobenzene (Example 166-b) (30.0 mg, 0.11 mmol) was dissolved in piperidine (183.0 mg, 2.14 mmol), followed by stirring at room temperature for 2 days. The reaction mixture was extracted with CH₂Cl₂, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 1-(2-(3-chloro-5-nitrophenyl)propan-2-yl)piperidine (35.0 mg, quant.) as a colorless liquid.

¹H-NMR (400 MHz, CDCl₃): δ 8.31 (s, 1H), 8.20 (s, 1H), 7.90 (s, 1H), 2.37 (t, 4H, J=4.3 Hz), 1.55 (t, 4H, J=5.2 Hz), 1.42-1.46 (m, 2H), 1.33 (s, 6H)

(b) Synthesis of 3-chloro-5-(2-(piperidin-1-yl)propan-2-yl)aniline

The synthesis procedure of Intermediate 40 was repeated except for using 1-(2-(3-chloro-5-nitrophenyl)propan-2-yl)piperidine (35.0 mg, 0.11 mmol) to obtain 3-chloro-5-(2-(piperidin-1-yl)propan-2-yl)aniline (25.0 mg, 90%).

LC/MS ESI (+): 253 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 6.90 (s, 1H), 6.79 (s, 1H), 6.52 (s, 1H), 3.67 (brs, 2H), 2.38 (brs, 4H), 1.48-1.54 (m, 4H), 1.40-1.43 (m, 2H), 1.25 (s, 6H)

(c) Synthesis of N-(3-chloro-5-(2-(piperidin-1-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-chloro-5-(2-(piperidin-1-yl)propan-2-yl)aniline (25.0 mg, 0.10 mmol) to obtain N-(3-chloro-5-(2-(piperidin-1-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (27.0 mg, 53%).

LC/MS ESI (+): 506 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.83 (s, 1H), 8.28 (s, 1H), 7.97 (d, 1H, J=8.7 Hz), 7.82 (s, 1H), 7.73-7.75 (m, 2H), 7.30 (d, 1H, J=8.7 Hz), 7.20 (s, 1H), 2.96 (s, 3H), 2.31 (brs, 4H), 1.44 (brs, 4H), 1.33 (brs, 2H), 1.21 (s, 6H)

Through the synthetic method according to Example 164, a compound of Example 165 was synthesized, and the data is as follows.

TABLE 9 Ex. Compound Analysis data 165 6-chloro-N-(3-chloro-5-(2- LC/MS ESI (+): 540 (M + 1) (piperidin-1-yl)propan-2- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.60 (s, 1H), 9.58 yl)phenyl)-5- (brs, 1H), 8.26~8.28 (m, 2H), 7.97 (s, 1H), 7.80 (s, 1H), (methylsulfonamido)benzo 7.73 (s, 1H), 7.21 (s, 1H), 2.98 (s, 3H), 2.27~2.34 (m, [b]thiophene-2- 4H), 1.39~1.46 (m, 4H), 1.32~1.34 (m, 2H), 1.21 (s, 6H) carboxamide

Example 166 Synthesis of N-(3-(2-(1H-pyrrol-2-yl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 1-chloro-3-nitro-5-(prop-1-en-2-yl)benzene

1-Bromo-3-chloro-5-nitrobenzene (5.0 g, 21.15 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolan (4.0 mL, 21.15 mmol), Pd(PPh₃)₄ (1.2 g, 1.06 mmol) and Na₂CO₃ (6.7 g, 63.44 mmol) were added to a mixture of DME/H₂O (105.0 mL, 2/1 v/v), followed by refluxing at 80° C. for 7 hours. The reaction mixture was cooled to room temperature and then extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain a mixture of 1-chloro-3-nitro-5-(prop-1-en-2-yl)benzene and 1-bromo-3-chloro-5-nitrobenzene (4.2 g) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃): δ 8.20 (m, 1H), 8.11 (m, 1H), 7.74 (m, 1H), 5.52 (s, 1H), 5.30 (m, 1H), 2.18-2.19 (m, 3H)

(b) Synthesis of 1-(2-bromopropan-2-yl)-3-chloro-5-nitrobenzene

A mixture of 1-chloro-3-nitro-5-(prop-1-en-2-yl)benzene and 1-bromo-3-chloro-5-nitrobenzene (4.2 g) was dissolved in anhydrous Et₂O (50.0 mL), and 33% solution of HBr in AcOH (25.9 mL, 147.76 mmol) was added at 0° C., followed by stirring at room temperature for 12 hours. A large amount of Et₂O was added, and an organic layer was washed with H₂O, sat. NaHCO₃ aqueous solution, and brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=20:1) to obtain 1-(2-bromopropan-2-yl)-3-chloro-5-nitrobenzene (3.0 g, 2 step yield: 51%) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃): δ 8.34 (m, 1H), 8.14 (m, 1H), 7.93 (m, 1H), 2.21 (s, 6H)

(c) Synthesis of 2-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-1H-pyrrole and 3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-1H-pyrrole

1-(2-Bromopropan-2-yl)-3-chloro-5-nitrobenzene (150 mg, 0.43 mmol) and pyrrole (1.1 mL, 16.17 mmol) were dissolved in 1,2-dichloroethane (5.4 mL), and AlCl₃ (215.6 mg, 1.62 mmol) was added at room temperature. The mixture was heated at 30° C. for 4 days, and water was added. The resulting reaction mixture was filtered through Celite and extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 2-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-1H-pyrrole (166-c-1) (37.2 mg, 33%) as a yellow oil and 3-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-1H-pyrrole (166-c-2) (20.0 mg, 18%) as a yellow solid.

(166-c-1) 2-(2-(3-Chloro-5-nitrophenyl)propan-2-yl)-1H-pyrrole

LC/MS ESI (+): 265 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.05, (m, 1H), 8.01 (m, 1H), 7.74 (brs, 1H), 7.47 (m, 1H), 6.73 (m, 1H), 6.18 (m, 1H), 6.13 (m, 1H), 1.72 (s, 6H)

(166-c-2) 3-(2-(3-Chloro-5-nitrophenyl)propan-2-yl)-1H-pyrrole

LC/MS ESI (+): 265 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.08-8.13 (m, 2H), 8.01 (m, 1H), 7.61 (m, 1H), 6.78 (m, 1H), 6.63 (m, 1H), 5.99 (m, 1H), 1.67 (s, 6H)

(d) Synthesis of 3-(2-(1H-pyrrol-2-yl)propan-2-yl)-5-chloroaniline

The synthesis procedure of Intermediate 40 was repeated except for using 2-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-1H-pyrrole (44.2 mg, 0.17 mmol) to obtain 3-(2-(1H-pyrrol-2-yl)propan-2-yl)-5-chloroaniline (35.0 mg, 89%).

LC/MS ESI (+): 235 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.69 (brs, 1H), 6.65-6.67 (m, 2H), 6.51 (m, 1H), 6.34 (m, 1H), 6.14 (m, 1H), 6.09 (m, 1H), 3.65 (s, 2H), 1.61 (s, 6H)

(e) Synthesis of N-(3-(2-(1H-pyrrol-2-yl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-(2-(1H-pyrrol-2-yl)propan-2-yl)-5-chloroaniline (35.0 mg, 0.15 mmol) to obtain N-(3-(2-(1H-pyrrol-2-yl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (35.1 mg, 56%).

LC/MS ESI (+): 488 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 10.48 (s, 1H), 9.89 (s, 1H), 8.30 (s, 1H), 8.02 (d, 1H, J=8.7 Hz), 7.84 (m, 1H), 7.80 (d, 1H, J=2.0 Hz), 7.53 (m, 1H), 7.36 (dd, 1H, J=8.7, 2.1 Hz), 6.89 (m, 1H), 6.63 (m, 1H), 5.91-5.94 (m, 2H), 3.01 (s, 3H), 1.61 (s, 6H)

Example 167 Synthesis of N-(3-(2-(1H-pyrrol-3-yl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 3-(2-(1H-pyrrol-3-yl)propan-2-yl)-5-chloroaniline

The synthesis procedure of Intermediate 13-c was repeated except for using 3-(2-(3-Chloro-5-nitrophenyl)propan-2-yl)-1H-pyrrole (Example 166-c-2) (20.0 mg, 0.08 mmol) to obtain 3-(2-(1H-pyrrol-3-yl)propan-2-yl)-5-chloroaniline (14.3 mg, 81%).

LC/MS ESI (+): 235 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.00 (brs, 1H), 6.72-6.75 (m, 2H), 6.58 (m, 1H), 6.47-6.50 (m, 2H), 6.04 (m, 1H), 3.62 (s, 2H), 1.58 (s, 6H)

(b) Synthesis of N-(3-(2-(1H-pyrrol-3-yl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-(2-(1H-pyrrol-3-yl)propan-2-yl)-5-chloroaniline (14.3 mg, 0.06 mmol) to obtain N-(3-(2-(1H-pyrrol-3-yl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (13.7 mg, 46%).

LC/MS ESI (+): 488 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.54-10.55 (m, 2H), 9.89 (s, 1H), 8.31 (s, 1H), 8.02 (d, 1H, J=8.7 Hz), 7.81 (m, 1H), 7.79 (d, 1H, J=2.0 Hz), 7.62 (m, 1H), 7.36 (dd, 1H, J=8.7, 2.1 Hz), 7.01 (m, 1H), 6.67 (m, 1H), 6.59 (m, 1H), 5.86 (m, 1H), 3.02 (s, 3H), 1.57 (s, 6H)

Through the synthetic method according to Examples 166 and 167, compounds from Example 168 to Example 185 were synthesized, and the data of each example are as follows.

TABLE 10 Ex. Compound Analysis data 168 N-(3-chloro-5-(2-(1-methyl- LC/MS ESI (+): 502 (M + 1) 1H-pyrrol-3-yl)propan-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.89 (s, yl)phenyl)-5- 1H), 8.31 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.83 (s, 1H), (methylsulfonamido)ben- 7.80 (s, 1H), 7.60 (s, 1H), 7.36 (d, 1H, J = 8.8 Hz), 7.02 (s, zo[b]thiophene-2-carboxamide 1H), 6.60 (s, 1H), 6.53 (s, 1H), 5.81 (s, 1H), 3.56 (s, 3H), 3.02 (s, 3H), 1.55 (s, 6H) 169 N-(3-chloro-5-(2-(1-methyl- LC/MS ESI (+): 502 (M + 1) 1H-pyrrol-2-yl)propan-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.59 (s, 1H), 9.87 (s, yl)phenyl)-5- 1H), 8.29 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.88 (s, 1H), (methylsulfonamido)ben- 7.79 (s, 1H), 7.49 (s, 1H), 7.36 (d, 1H, J = 8.7 Hz), 6.88 (s, zo[b]thiophene-2-carboxamide 1H), 6.61 (s, 1H), 6.10 (s, 1H), 5.94 (s, 1H), 3.09 (s, 3H), 3.01 (s, 3H), 1.61 (s, 6H) 170 N-(3-chloro-5-(2-(thiophen- LC/MS ESI (+): 505 (M + 1) 2-yl)propan-2-yl)phenyl)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.86 (s, (methylsulfonamido)ben- 1H), 8.30 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.88 (s, 1H), zo[b]thiophene-2-carboxamide 7.80 (s, 1H), 7.65 (s, 1H), 7.35~7.40 (m, 2H), 7.08 (s, 1H), 6.97~6.99 (m, 2H), 3.02 (s, 3H), 1.74 (s, 6H) 171 N-(3-chloro-5-(2-(thiophen- LC/MS ESI (+): 505 (M + 1) 3-yl)propan-2-yl)phenyl)-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.87 (brs, (methylsulfonamido)ben- 1H), 8.29 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.85 (s, 1H), zo[b]thiophene-2-carboxamide 7.79 (m, 1H), 7.57 (s, 1H), 7.46 (dd, 1H, J = 4.9, 2.9 Hz), 7.36 (dd, 1H, J = 8.8, 1.5 Hz), 7.31 (m, 1H), 6.99 (s, 1H), 6.90 (d, 1H, J = 4.9 Hz), 3.01 (s, 3H), 1.65 (s, 6H) 172 6-chloro-N-(3-chloro-5-(2- LC/MS ESI (+): 567 (M + 1) (4-chlorophenyl)propan-2- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H), 9.62 (s, yl)phenyl)-5- 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.03 (s, 1H), 7.87 (s, 1H), (methylsulfonamido)ben- 7.48 (s, 1H), 7.37 (d, 2H, J = 8.6 Hz), 7.27(d, 2H, J = 8.6 Hz), zo[b]thiophene-2-carboxamide 7.03 (s, 1H), 3.06 (s, 3H), 1.64 (s, 6H) 173 6-bromo-N-(3-chloro-5-(2- LC/MS ESI (+): 611 (M + 1) (4-chlorophenyl)propan-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.63 (s, 1H), 9.55 (s, yl)phenyl)-5- 1H), 8.50 (s, 1H), 8.27 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H), (methylsulfonamido)ben- 7.48 (s, 1H), 7.37 (d, 2H, J = 8.6 Hz), 7.27(d, 2H, J = 8.6 Hz), zo[b]thiophene-2-carboxamide 7.04 (s, 1H), 3.07 (s, 3H), 1.64 (s, 6H) 174 N-(3-chloro-5-(2-(5- LC/MS ESI(+): 539 (M + 1) chlorothiophen-2- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.58 (s, m), 9.90 (s, yl)propan-2-yl)phenyl)-5- 1H), 8.29 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.90 (s, 1H), (methylsulfonamido)ben- 7.78 (s, 1H), 7.63 (s, 1H), 7.34 (d, 1H, J = 8.7 Hz), 7.12 (s, zo[b]thiophene-2-carboxamide 1H), 6.98 (d, 1H, J = 3.9 Hz), 6.85 (d, 1H, J = 3.9 Hz), 3.00 (s, 3H), 1.70 (s, 6H) 175 6-chloro-N-(3-chloro-5-(2- LC/MS ESI (+): 573 (M + 1) (5-chlorothiophen-2- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H), 9.69 (s, yl)propan-2-yl)phenyl)-5- 1H), 8.26 (s, 2H), 7.98 (s, 1H), 7.90 (s, 1H), 7.62 (s, 1H), (methylsulfonamido)ben- 7.13 (s, 1H), 6.98 (d, 1H, J = 3.8 Hz), 6.85 (d, 1H, zo[b]thiophene-2-carboxamide J = 3.8 Hz), 2.98 (s, 3H), 1.70 (s, 6H) 176 N-(3-chloro-5-(2-(2- LC/MS ESI (+): 535 (M + 1) methoxythiophen-3- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.89 (brs, yl)propan-2-yl)phenyl)-5- 1H), 8.30 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.84 (s, 1H), (methylsulfonamido)ben- 7.79 (s, 1H), 7.55 (s, 1H), 7.35 (dd, 1H, J = 8.7, 1.5 Hz), zo[b]thiophene-2-carboxamide 6.97 (s, 1H), 6.78~6.82 (m, 2H), 3.63 (s, 3H), 3.01 (s, 3H), 1.62 (s, 6H) 177 N-(3-chloro-5-(2-(5- LC/MS ESI (+): 535 (M + 1) methoxythiophen-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.88 (brs, yl)propan-2-yl)phenyl)-5- 1H), 8.29 (s, 1H), 8.00 (d, 1H, J = 8.8 Hz), 7.87 (s, 1H), (methylsulfonamido)ben- 7.78 (s, 1H), 7.62 (s, 1H), 7.34 (dd, 1H, J = 8.7, 2.1 Hz), zo[b]thiophene-2-carboxamide 7.06 (s, 1H), 6.57 (d, 1H, J = 3.9 Hz), 6.10 (d, 1H, J = 3.9 Hz), 3.78 (s, 3H), 3.00 (s, 3H), 1.65 (s, 6H) 178 N-(3-chloro-5-(2-(5- LC/MS ESI (+): 519 (M + 1) methylthiophen-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.89 (brs, yl)propan-2-yl)phenyl)-5- 1H), 8.30 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 7.88 (m, 1H), (methylsulfonamido)ben- 7.80 (m, 1H), 7.64 (m, 1H), 7.36 (dd, 1H, J = 8.7, 2.1 Hz), zo[b]thiophene-2-carboxamide 7.07 (m, 1H), 6.74 (d, 1H, J = 3.4 Hz), 6.63 (m, 1H), 3.01 (s, 3H), 2.37 (s, 3H), 1.69 (s, 6H) 179 6-chloro-N-(3-chloro-5-(2- LC/MS ESI (+): 553 (M + 1) (5-methylthiophen-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.66 (s, 1H), 9.64 (s, yl)propan-2-yl)phenyl)-5- 1H), 8.34 (s, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.87 (m, 1H), (methylsulfonamido)ben- 7.62 (m, 1H), 7.08 (m, 1H), 6.74 (d, 1H, J = 3.5 Hz), 6.63 zo[b]thiophene-2-carboxamide (m, 1H), 3.05 (s, 3H), 2.37 (s, 3H), 1.69 (s, 6H) 180 6-chloro-N-(3-chloro-5-(2- LC/MS ESI (+): 581 (M + 1) (5-isopropylthiophen-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.69 (s, 1H), 9.64 (s, yl)propan-2-yl)phenyl)-5- 1H), 8.36 (s, 1H), 8.32 (s, 1H), 8.05 (s, 1H), 7.88 (m, 1H), (methylsulfonamido)ben- 7.64 (m, 1H), 7.09 (m, 1H), 6.74 (d, 1H, J = 3.5 Hz), 6.67 zo[b]thiophene-2-carboxamide (dd, 1H, J = 3.5, 0.8 Hz), 3.02~3.09 (m, 4H), 1.70 (s, 6H), 1.22 (d, 6H, J = 6.8 Hz) 181 6-chloro-N-(3-chloro-5-(2- LC/MS ESI (+): 553 (M + 1) (4-methylthiophen-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.66 (s, 1H), 9.64 (s, yl)propan-2-yl)phenyl)-5- 1H), 8.33 (s, 1H), 8.30 (s, 1H), 8.02 (s, 1H), 7.88 (m, 1H), (methylsulfonamido)ben- 7.62 (m, 1H), 7.09 (m, 1H), 6.95 (m, 1H), 6.77 (d, 1H, zo[b]thiophene-2-carboxamide J = 1.3 Hz), 3.04 (s, 3H), 2.17 (d, 3H, J = 0.9 Hz), 1.70 (s, 6H) 182 6-chloro-N-(3-chloro-5-(2- LC/MS ESI (+): 551 (M + 1) (4-fluorophenyl)propan-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.64 (s, 1H), 9.64 (brs, yl)phenyl)-5- 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.04 (s, 1H), 7.87 (s, 1H), (methylsulfonamido)ben- 7.49 (s, 1H), 7.28 (dd, 2H, J = 8.4, 5.7 Hz), 7.13 (t, 2H, zo[b]thiophene-2-carboxamide J = 8.8 Hz), 7.03 (s, 1H), 3.06 (s, 3H), 1.64 (s, 6H) 183 6-chloro-N-(3-chloro-5-(2- LC/MS ESI (+): 563 (M + 1) (4-methoxyphenyl)propan- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 1H), 9.65 2-yl)phenyl)-5- (brs, 1H), 8.35 (s, 1H), 8.30 (s, 1H), 8.03 (s, 1H), 7.87 (s, (methylsulfonamido)ben- 1H), 7.51 (s, 1H), 7.17 (d, 2H, J = 8.8 Hz), 7.00 (s, 1H), zo[b]thiophene-2-carboxamide 6.88 (d, 2H, J = 8.8 Hz), 3.74 (s, 3H), 3.06 (s, 3H), 1.63 (s, 6H) 184 5-chloro-N-(3-chloro-5-(2- LC/MS ESI (+): 567 (M + 1) (4-chlorophenyl)propan-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.65 (s, 1H), 9.68 (brs, yl)phenyl)-6- 1H), 8.23 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.88 (m, 1H), (methylsulfonamido)ben- 7.49 (m, 1H), 7.37 (d, 2H, J = 8.7 Hz), 7.27 (d, 2H, zo[b]thiophene-2-carboxamide J = 8.7 Hz), 7.03 (m, 1H), 3.09 (s, 3H), 1.64 (s, 6H) 185 6-chloro-N-(3-chloro-5-(2- LC/MS ESI (+): 611 (M + 1) (4-chlorophenyl)propan-2- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H), 9.67 yl)phenyl)-5-((2- (brs, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), 7.89 (s, methoxyethyl)sulfonamido) 1H), 7.49 (s, 1H), 7.39 (d, 2H, J = 8.8 Hz), 7.28 (d, 2H, benzo[b]thiophene-2- J = 8.8 Hz), 7.05 (s, 1H), 3.74 (t, 2H, J = 6.4 Hz), 3.47~3.41 carboxamide (m, 2H), 3.24 (s, 3H), 1.65 (s, 6H)

Example 186 Synthesis of 6-chloro-N-(3-chloro-5-(2-(5-cyanothiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 5-(2-(3-chloro-5-nitrophenyl)propan-2-yl)thiophene-2-carbonitrile

2-Bromo-5-(2-(3-chloro-5-nitrophenyl)propan-2-yl)thiophene (250.0 mg, 0.69 mmol) and CuCN (62.0 mg, 0.69 mmol) were dissolved in anhydrous DMF (1.0 mL), and the reaction temperature was increased to 140° C., followed by stirring for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=7:1) to obtain 5-(2-(3-chloro-5-nitrophenyl)propan-2-yl)thiophene-2-carbonitrile (56.0 mg, 26%) as a yellow liquid.

¹H-NMR (400 MHz, CDCl₃): δ 8.21 (s, 1H), 8.07 (s, 1H), 7.56 (s, 1H), 7.51 (d, 1H, J=4.0 Hz), 6.85 (d, 1H, J=4.0 Hz), 1.84 (s, 6H)

(b) Synthesis of 5-(2-(3-amino-5-chlorophenyl)propan-2-yl)thiophene-2-carbonitrile

The synthesis procedure of Intermediate 40 was repeated except for using 5-(2-(3-chloro-5-nitrophenyl)propan-2-yl)thiophene-2-carbonitrile (54.0 mg, 0.18 mmol) to obtain 5-(2-(3-amino-5-chlorophenyl)propan-2-yl)thiophene-2-carbonitrile (35.0 mg, 72%).

LC/MS ESI (+): 277 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.45 (d, 1H, J=4.0 Hz), 6.81 (d, 1H, J=4.0 Hz), 6.65 (s, 1H), 6.56 (s, 1H), 6.41 (s, 1H), 3.72 (brs, 2H), 1.72 (s, 6H)

(c) Synthesis of 6-chloro-N-(3-chloro-5-(2-(5-cyanothiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 5-(2-(3-Amino-5-chlorophenyl)propan-2-yl)thiophene-2-carbonitrile (35.0 mg, 0.13 mmol) to obtain 6-chloro-N-(3-chloro-5-(2-(5-cyanothiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (10.0 mg, 14%).

LC/MS ESI (+): 564 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.59 (s, 1H), 9.59 (brs, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.84 (s, 1H), 7.80 (d, 1H, J=3.6 Hz), 7.54 (s, 1H), 7.11-7.12 (m, 2H), 2.95 (s, 3H), 1.71 (s, 6H)

Example 187 Synthesis of N-(3-chloro-5-(2-(1-ethyl-1H-pyrrol-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 2-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-1-ethyl-1H-pyrrole

2-(2-(3-Chloro-5-nitrophenyl)propan-2-yl)-1H-pyrrole (66.0 mg, 0.25 mmol) was dissolved in anhydrous DMF (5.0 mL), and 60% NaH in mineral oil (11.0 mg, 0.28 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, and ethyl iodide (57.0 mg, 0.37 mmol) was added. The reaction mixture was stirred at room temperature for 1 hours and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 2-(2-(3-chloro-5-nitrophenyl)propan-2-yl)-1-ethyl-1H-pyrrole (47.0 mg, 64%) as a yellow liquid.

¹H-NMR (400 MHz, CDCl₃): δ 8.05 (s, 1H), 8.00 (s, 1H), 7.43 (s, 1H), 6.67 (t, 1H, J=2.4 Hz), 6.17 (d, 2H, J=2.4 Hz), 3.37 (q, 2H, J=7.2 Hz), 1.70 (s, 6H), 1.08 (t, 3H, J=7.2 Hz)

(b) Synthesis of 3-chloro-5-(2-(1-ethyl-1H-pyrrol-2-yl)propan-2-yl)aniline

The synthesis procedure of Intermediate 40 was repeated except for using 2-(2-(3-Chloro-5-nitrophenyl)propan-2-yl)-1-ethyl-1H-pyrrole (47.0 mg, 0.16 mmol) to obtain 3-chloro-5-(2-(1-ethyl-1H-pyrrol-2-yl)propan-2-yl)aniline (31.0 mg, 73%).

LC/MS ESI (+): 263 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 6.62-6.64 (m, 2H), 6.50 (s, 1H), 6.29 (s, 1H), 6.13 (t, 1H, J=2.8 Hz), 6.10 (m, 1H), 3.64 (brs, 2H), 3.45 (q, 2H, J=7.2 Hz), 1.60 (s, 6H), 1.09 (t, 3H, J=7.2 Hz)

(c) Synthesis of N-(3-chloro-5-(2-(1-ethyl-1H-pyrrol-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-chloro-5-(2-(1-ethyl-1H-pyrrol-2-yl)propan-2-yl)aniline (31.0 mg, 0.12 mmol) to obtain N-(3-chloro-5-(2-(1-ethyl-1H-pyrrol-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (30.0 mg, 50%).

LC/MS ESI (+): 516 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.60 (s, 1H), 9.87 (brs, 1H), 8.31 (s, 1H), 8.03 (d, 1H, J=8.8 Hz), 7.89 (s, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 7.37 (d, 1H, J=8.8 Hz), 6.90 (s, 1H), 6.74 (s, 1H), 6.05 (m, 1H), 6.02 (m, 1H), 3.42 (q, 2H, J=7.2 Hz), 3.02 (s, 3H), 1.62 (s, 6H), 0.98 (t, 3H, J=7.2 Hz)

Example 188 Synthesis of 6-chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-((2-hydroxyethyl)sulfonamido)benzo[b]thiophene-2-carboxamide

6-Chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-((2-methoxyethyl)sulfonamido)benzo[b]thiophene-2-carboxamide (63.0 mg, 0.10 mmol) was dissolved in toluene (1.0 mL), and 1.0M BBr₃ dissolved in CH₂Cl₂ (30.6 μL, 0.31 mmol) was slowly added at 0° C. The reaction temperature was increased to room temperature, and the reaction mixture was stirred for 15 hours and extracted with EtOAc. The organic extract was washed with water, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH₃CN:0.1% formic acid in H₂O=7:3) to obtain 6-chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-((2-hydroxyethyl)sulfonamido)benzo[b]thiophene-2-carboxamide (34.0 mg, 56%) as a white solid.

LC/MS ESI (+): 597 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H), 9.62 (brs, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 7.49 (s, 1H), 7.39 (d, 2H, J=8.8 Hz), 7.28 (d, 2H, J=8.8 Hz), 7.05 (s, 1H), 5.04 (brs, 1H), 3.80-3.84 (m, 2H), 3.30-3.32 (m, 2H), 1.65 (s, 6H)

Example 189 Synthesis of N-(3-chloro-5-(2-(pyrimidin-2-yloxy)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 2-((2-(3-chloro-5-nitrophenyl)propan-2-yl)oxy)pyrimidine

1-(2-Bromopropan-2-yl)-3-chloro-5-nitrobenzene (Example 166-b) (24.0 mg, 0.09 mmol) was dissolved in anhydrous DMF (0.9 mL), and K₂CO₃ (24.0 mg, 0.17 mmol) and pyrimidine-4(3H)-one (17.0 mg, 0.17 mmol) were added at room temperature. The mixture was stirred at room temperature for 15 hours, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, EtOAc) to obtain 2-((2-(3-chloro-5-nitrophenyl)propan-2-yl)oxy)pyrimidine (11.0 mg, 44%) as a colorless liquid.

¹H-NMR (400 MHz, CDCl₃): δ 8.57 (s, 1H), 8.11 (s, 1H), 7.92-7.97 (m, 2H), 7.47 (s, 1H), 6.34 (d, 1H, J=6.5 Hz), 1.99 (s, 6H)

(b) Synthesis of 3-chloro-5-(2-(pyrimidin-2-yloxy)propan-2-yl)aniline

The synthesis procedure of Intermediate 40 was repeated except for using 2-((2-(3-chloro-5-nitrophenyl)propan-2-yl)oxy)pyrimidine (11.0 mg, 0.04 mmol) to obtain 3-chloro-5-(2-(pyrimidin-2-yloxy)propan-2-yl)aniline (4.0 mg, 38%).

LC/MS ESI (+): 264 (M+1)

(c) Synthesis of N-(3-chloro-5-(2-(pyrimidin-2-yloxy)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-chloro-5-(2-(pyrimidin-2-yloxy)propan-2-yl)aniline (4.0 mg, 0.01 mmol) to obtain N-(3-chloro-5-(2-(pyrimidin-2-yloxy)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (2.0 mg, 35%).

LC/MS ESI (+): 517 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.51 (s, 1H), 9.85 (brs, 1H), 8.75 (s, 1H), 8.21 (s, 1H), 7.97 (d, 1H, J=6.5 Hz), 7.87-7.90 (m, 2H), 7.68 (s, 1H), 7.43 (s, 1H), 7.26 (d, 1H, J=8.1 Hz), 7.01 (s, 1H), 6.29 (d, 1H, J=6.5 Hz), 2.89 (s, 3H), 1.89 (s, 6H)

Example 190 Synthesis of N-(3-chloro-5-(2-(6-oxopyridazin-1(6H)-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 2-(2-(3-chloro-5-nitrophenyl)propan-2-yl)pyridazin-3(2H)-one

1-(2-Bromopropan-2-yl)-3-chloro-5-nitrobenzene (Example 166-b) (24.0 mg, 0.09 mmol) was dissolved in anhydrous DMF (0.9 mL), and K₂CO₃ (24.0 mg, 0.17 mmol) and pyridazin-3(2H)-one (17.0 mg, 0.17 mmol) were added at room temperature. The mixture was stirred at room temperature for 15 hours, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain 2-(2-(3-chloro-5-nitrophenyl)propan-2-yl)pyridazin-3(2H)-one (13.0 mg, 51%) as a colorless liquid.

¹H-NMR (400 MHz, CDCl₃): δ 8.07 (s, 1H), 7.94 (s, 1H), 7.89 (s, 1H), 7.50 (s, 1H), 7.24 (d, 1H, J=3.7 Hz), 6.80 (d, 1H, J=9.3 Hz), 1.93 (s, 6H)

(b) Synthesis of 2-(2-(3-amino-5-chlorophenyl)propan-2-yl)pyridazin-3(2H)-one

The synthesis procedure of Intermediate 40 was repeated except for using 2-(2-(3-chloro-5-nitrophenyl)propan-2-yl)pyridazin-3(2H)-one (13.0 mg, 0.05 mmol) to obtain 2-(2-(3-amino-5-chlorophenyl)propan-2-yl)pyridazin-3(2H)-one (2.0 mg, 15%).

LC/MS ESI (+): 264 (M+1)

(c) Synthesis of N-(3-chloro-5-(2-(6-oxopyridazin-1(6H)-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 2-(2-(3-amino-5-chlorophenyl)propan-2-yl)pyridazin-3(2H)-one (2.0 mg, 0.01 mmol) to obtain N-(3-chloro-5-(2-(6-oxopyridazin-1(6H)-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (3.0 mg, 72%).

LC/MS ESI (+): 517 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.87 (brs, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 8.01 (d, 1H, J=8.7 Hz), 7.87 (s, 1H), 7.78 (s, 1H), 7.48 (dd, 1H, J=9.3, 3.8 Hz), 7.40 (s, 1H), 7.35 (d, 1H, J=8.7 Hz), 6.96 (s, 1H), 6.83 (d, 1H, J=9.3 Hz), 3.00 (s, 3H), 1.83 (s, 6H)

Example 191 Synthesis of N-(3-chloro-5-(2-(pyridin-4-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 3-chloro-5-methoxybenzonitrile

3,5-Dichlorobenzonitrile (1.5 g, 8.72 mmol) was dissolved in anhydrous DMF (10.0 mL), and 35% solution of NaOMe in MeOH (4.0 mL) was slowly added, followed by stirring for 72 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:3) to obtain 3-chloro-5-methoxybenzonitrile (970.0 mg, 63%) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ 7.23 (t, 1H, J=1.6 Hz), 7.12 (t, 1H, J=2.0 Hz), 7.05 (dd, 1H, J=2.4, 1.2 Hz), 3.84 (s, 3H)

(b) Synthesis of (3-chloro-5-methoxyphenyl)(pyridin-4-yl)methanone

4-Bromopyridine (1.8 g, 11.4 mmol) was dissolved in Et₂O (7.5 mL), and n-BuLi (9.8 mL, 15.7 mmol) was slowly added at −78° C. and stirred for 1 hour. 3-Chloro-5-methoxybenzonitrile (1.2 g, 7.16 mmol) was dissolved in Et₂O (10.0 mL) and added to the reaction mixture, followed by stirring at 0° C. for 12 hours. The reaction was quenched with 1 N HCl, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:CH₂Cl₂=1:1) to obtain (3-chloro-5-methoxyphenyl)(pyridin-4-yl)methanone (950.0 mg, 56%) as an off-white oil.

LC/MS ESI (+): 248 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.83 (d, 2H, J=5.2 Hz), 7.58 (d, 2H, J=6.0 Hz), 7.32 (t, 1H, J=1.6 Hz), 7.24 (s, 1H), 7.17 (t, 1H, J=2.0 Hz), 3.86 (s, 3H)

(c) Synthesis of 4-(dichloro(3-chloro-5-methoxyphenyl)methyl)pyridine

The synthesis procedure of Intermediate 37 was repeated except for using (3-chloro-5-methoxyphenyl)(pyridin-4-yl)methanone (950.0 mg, 2.55 mmol) to obtain 4-(dichloro(3-chloro-5-methoxyphenyl)methyl)pyridine (510.0 mg, 43%).

LC/MS ESI (+): 302 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.68 (d, 2H, J=6.0 Hz), 7.51 (d, 2H, J=6.0 Hz), 7.15 (s, 1H), 7.02 (t, 1H, J=2.0 Hz), 6.91 (t, 1H, J=2.0 Hz), 3.80 (s, 3H)

(d) Synthesis of 4-(2-(3-chloro-5-methoxyphenyl)propan-2-yl)pyridine

The synthesis procedure of Intermediate 38 was repeated except for using 4-(dichloro(3-chloro-5-methoxyphenyl)methyl)pyridine (200.0 mg, 0.66 mmol) to obtain 4-(2-(3-chloro-5-methoxyphenyl)propan-2-yl)pyridine (71.4 mg, 41%).

LC/MS ESI (+): 262 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.52 (brs, 2H), 7.13 (brs, 2H), 6.78 (t, 1H, J=1.6 Hz), 6.75 (t, 1H, J=2.0 Hz), 6.61 (t, 1H, J=2.0 Hz), 3.75 (s, 3H), 1.64 (s, 6H)

(f) Synthesis of 3-chloro-5-(2-(pyridin-4-yl)propan-2-yl)phenol

The synthesis procedure of Intermediate 41 was repeated except for using 4-(2-(3-chloro-5-methoxyphenyl)propan-2-yl)pyridine (183.0 mg, 0.49 mmol) to obtain 3-chloro-5-(2-(pyridin-4-yl)propan-2-yl)phenol (157.0 mg, 91%).

LC/MS ESI (+): 248 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.37 (d, 2H, J=5.2 Hz), 7.15 (d, 2H, J=5.2 Hz), 6.87 (s, 1H), 6.76 (s, 1H), 6.30 (s, 1H), 1.63 (s, 6H)

(g) Synthesis of 3-chloro-5-(2-(pyridin-4-yl)propan-2-yl)phenyl trifluoromethanesulfonate

The synthesis procedure of Example 114-a was repeated except for using 3-chloro-5-(2-(pyridin-4-yl)propan-2-yl)phenol (80.0 mg, 0.32 mmol) to obtain 3-chloro-5-(2-(pyridin-4-yl)propan-2-yl)phenyl trifluoromethanesulfonate (40.0 mg, 33%).

LC/MS ESI (+): 380 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.55 (d, 2H, J=5.2 Hz), 7.21 (s, 1H), 7.18 (s, 1H), 7.10 (d, 2H, J=5.2 Hz), 6.99 (s, 1H), 1.68 (s, 6H)

(h) Synthesis of 3-chloro-5-(2-(pyridin-4-yl)propan-2-yl)aniline

3-Chloro-5-(2-(pyridin-4-yl)propan-2-yl)phenyl trifluoromethanesulfonate (40.0 mg, 0.11 mmol), benzophenone imine (21.0 μL, 0.13 mmol), Pd₂dba₃CHCl₃ (11.0 mg, 0.01 mmol), rac-BINAP (13.7 mg, 0.02 mmol), and Cs₂CO₃ (51.3 mg, 0.16 mmol) were dissolved in THF (3.0 mL), followed by refluxing for 2 days. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was dissolved in THF (2.0 mL), and 2 N HCl aqueous solution (0.5 mL) was added, followed by stirring at room temperature for 3 hours. The reaction mixture was extracted with CH₂Cl₂, washed with sat. NaHCO₃ aqueous solution, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=20:1) to obtain 3-chloro-5-(2-(pyridin-4-yl)propan-2-yl)aniline (6.8 mg, 2 step yield: 26%) as a yellow liquid.

LC/MS ESI (+): 247 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 8.50 (m, 2H), 7.13 (d, 2H, J=5.6 Hz), 6.60 (m, 1H), 6.54 (m, 1H), 6.31 (m, 1H), 3.68 (brs, 2H), 1.61 (s, 6H)

(i) Synthesis of N-(3-chloro-5-(2-(pyridin-4-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-Chloro-5-(2-(pyridin-4-yl)propan-2-yl)aniline (6.0 mg, 0.02 mmol) to obtain N-(3-chloro-5-(2-(pyridin-4-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (3.3 mg, 28%).

LC/MS ESI (+): 500 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 9.88 (brs, 1H), 8.51 (d, 2H, J=5.6 Hz), 8.29 (s, 1H,), 8.03 (d, 1H, J=8.4 Hz), 7.91 (s, 1H), 7.80 (s, 1H), 7.52 (s, 1H), 7.37 (dd, 1H, J=8.8, 2.0 Hz), 7.27 (d, 2H, J=6.4 Hz), 7.07 (s, 1H), 3.02 (s, 3H), 1.67 (s, 6H)

Example 192 Synthesis of 2-((3-bromo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl dihydrogen phosphate (a) Synthesis of methyl 5-methoxybenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 14-1 was repeated except for using 2-fluoro-5-methoxybenzaldehyde (900.0 mg, 5.84 mmol) to obtain methyl 5-methoxybenzo[b]thiophene-2-carboxyle (270.0 mg, 21%).

LC/MS ESI (+): 223 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.96 (s, 1H), 7.69 (d, 1H, J=8.9 Hz), 7.25 (d, 1H, J=2.4 Hz), 7.09 (dd, 1H, J=8.9, 2.4 Hz), 3.92 (s, 3H), 3.86 (s, 3H)

(b) Synthesis of methyl 5-hydroxybenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 42 was repeated except for using methyl 5-methoxybenzo[b]thiophene-2-carboxylate (261.0 mg, 1.17 mmol) to obtain methyl 5-hydroxybenzo[b]thiophene-2-carboxylate (192.0 mg, 79%).

LC/MS ESI (+): 209 (M+1)

(c) Synthesis of 5-hydroxybenzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 13-d was repeated except for using methyl 5-hydroxybenzo[b]thiophene-2-carboxylate (191.0 mg, 0.92 mmol) to obtain 5-hydroxybenzo[b]thiophene-2-carboxylic acid (180.0 mg, 99%).

LC/MS ESI (+): 195 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 13.28 (brs, 1H), 9.62 (s, 1H), 7.79 (d, 1H, J=8.8 Hz), 7.30 (s, 1H), 7.00 (d, 1H, J=8.8 Hz)

(d) Synthesis of N-(3-bromo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-hydroxybenzo[b]thiophene-2-carboxamide

The synthesis procedure of Intermediate 13-d was repeated except for using 5-hydroxybenzo[b]thiophene-2-carboxylic acid (30 mg, 0.15 mmol) to obtain N-(3-bromo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-hydroxybenzo[b]thiophene-2-carboxamide (15.0 mg, 16%).

LC/MS ESI (+): 608 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.65-7.79 (m, 3H), 7.22-7.24 (m, 2H), 7.18-7.19 (m, 1H), 7.00-7.04 (m, 1H), 6.98-6.99 (m, 1H), 6.61-6.63 (m, 2H), 6.55-6.59 (m, 1H), 5.50 (brs, 1H), 4.40-4.49 (m, 1H), 1.60 (s, 6H), 1.29 (d, 6H, J=6.0 Hz)

(e) Synthesis of 2-((3-bromo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl dihydrogen phosphate

N-(3-bromo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-hydroxybenzo[b]thiophene-2-carboxamide (13.9 mg, 0.02 mmol) was dissolved in anhydrous THF (1.5 mL), and Et₃N (38.0 μL, 0.23 mmol) and POCl₃ (22.0 μL, 0.23 mmol) were added. After stirring at room temperature for 2 hours, cold H₂O (1.0 mL) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, CH₃CN:H₂O=4:6) to obtain 2-((3-bromo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl dihydrogen phosphate (2.0 mg, 13%) as a white solid.

LC/MS ESI (+): 688 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 8.20 (s, 1H), 8.02 (s, 1H), 7.84 (d, 1H, J=8.7 Hz), 7.72 (s, 1H), 7.60 (s, 1H), 7.32 (d, 1H, J=8.7 Hz), 7.13 (s, 1H), 6.76 (s, 1H), 6.71 (s, 1H), 6.70 (s, 1H), 4.55-4.68 (m, 1H), 1.63 (s, 6H), 1.22 (d, 6H, J=5.5 Hz)

Example 193 Synthesis of 2-((3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl dihydrogen phosphate

The synthesis procedure of Example 192 was repeated except for using methyl 5-hydroxybenzo[b]thiophene-2-carboxylate (86.7 mg, 0.45 mmol) to obtain 2-((3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl dihydrogen phosphate (5.0 mg).

LC/MS ESI (+): 644 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.59 (s, 1H), 8.26 (s, 1H), 8.00 (d, 1H, J=8.7 Hz), 7.90 (s, 1H), 7.74 (s, 1H), 7.54 (s, 1H), 7.32 (d, 1H, J=8.7 Hz), 7.03 (s, 1H), 6.75 (s, 1H), 6.72 (s, 1H), 6.71 (s, 1H), 4.59-4.65 (m, 1H), 1.64 (s, 6H), 1.23 (d, 6H, J=5.5 Hz)

Example 194 Synthesis of tert-butyl (2-((3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl)carbamate (a) Synthesis of ethyl 5-((tert-butoxycarbonyl)amino)benzo[b]thiophene-2-carboxylate

Ethyl 5-aminobenzo[b]thiophene-2-carboxylate (500.0 mg, 2.26 mmol), Boc₂O (592.0 mg, 2.71 mmol) was dissolved in THF (45.0 mL), followed by refluxing for 18 hours. The reaction mixture was extracted with EtOAc, washed with 1 N HCl aqueous solution, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain ethyl 5-((tert-butoxycarbonyl)amino)benzo[b]thiophene-2-carboxylate (684.8 mg, 94%) as a red solid.

¹H-NMR (400 MHz, CDCl₃): δ 8.04 (s, 1H), 7.97 (s, 1H), 7.74 (d, 1H, J=8.8 Hz), 7.33 (dd, 1H, J=8.8, 2.4 Hz), 6.57 (s, 1H), 4.40 (q, 2H, J=7.2 Hz), 1.54 (s, 9H), 1.41 (t, 3H, J=7.2 Hz)

(b) Synthesis of 5-((tert-butoxycarbonyl)amino)benzo[b]thiophene-2-carboxylic acid

Ethyl 5-((tert-butoxycarbonyl)amino)benzo[b]thiophene-2-carboxylate (684.0 mg, 2.13 mmol) was dissolved in MeOH (3.0 mL), and 2 N NaOH aqueous solution (2.13 mL) was added, followed by heating at 60° C. for 2 hours and 30 minutes. The reaction mixture was concentrated under reduced pressure. H₂O was added to the resulting residue to dilute, and 1 N HCl aqueous solution was added for acidification to pH 1-2. The precipitate was filtered. The pale red solid was dried to obtain 5-((tert-butoxycarbonyl)amino)benzo[b]thiophene-2-carboxylic acid (603.0 mg, 97%).

¹H-NMR (400 MHz, DMSO-d₆): δ 9.53 (s, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.88 (d, 1H, J=8.8 Hz), 7.46 (dd, 1H, J=8.8, 2.0 Hz), 1.49 (s, 9H)

(c) Synthesis of tert-butyl (2-((3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl)carbamate

The synthesis procedure of Intermediate 13-c was repeated except for using 5-((tert-butoxycarbonyl)amino)benzo[b]thiophene-2-carboxylic acid (603.0 mg, 2.06 mmol) to obtain tert-butyl (2-((3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl)carbamate (1.1 g, 77%).

LC/MS ESI (+): 663 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.54 (s, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 7.91-7.93 (m, 2H), 7.54-7.56 (m, 2H), 7.05 (s, 1H), 6.78 (s, 1H), 6.73 (s, 1H), 6.72 (s, 1H), 4.61-4.67 (m, 1H), 1.65 (s, 6H), 1.51 (s, 9H), 1.25 (d, 6H, J=6.0 Hz)

Example 195 Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((2-methoxyethyl)sulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 5-amino-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide

tert-Butyl (2-((3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl)carbamate (Example 194) (930.0 mg, 1.40 mmol) was dissolved in CH₂Cl₂ (14.0 mL), and TFA (1.4 mL) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was extracted with CH₂Cl₂, washed with sat. NaHCO₃ aqueous solution and brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain 5-amino-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide (734.0 mg, 93%) as a yellow liquid.

¹H-NMR (400 MHz, CDCl₃): δ 7.74-7.75 (m, 1H), 7.70 (s, 1H), 7.67 (brs, 1H), 7.63 (d, 1H, J=8.4 Hz), 7.19-7.20 (m, 1H), 7.11 (d, 1H, J=2.0 Hz), 7.00-7.01 (m, 1H), 6.90 (dd, 1H, J=8.4, 2.0 Hz), 6.65 (d, 2H, J=2.4 Hz), 6.59 (s, 1H), 4.44-4.51 (m, 1H), 3.79 (s, 2H), 1.65 (s, 6H), 1.31 (d, 6H, J=6.0 Hz)

(b) Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((2-methoxyethyl)sulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Intermediate 13-c was repeated except for using 5-amino-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide (40.0 mg, 0.07 mmol) to obtain N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((2-methoxyethyl)sulfonamido)benzo[b]thiophene-2-carboxamide (36.6 mg, 75%).

LC/MS ESI (+): 685 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.93 (s, 1H), 8.29 (s, 1H), 8.02 (d, 1H, J=8.8 Hz), 7.91 (m, 1H), 7.80 (m, 1H), 7.55 (s, 1H), 7.36 (dd, 1H, J=8.8, 2.1 Hz), 7.06 (m, 1H), 6.78 (s, 1H), 6.73 (s, 1H), 6.72 (s, 1H), 4.62-4.65 (m, 1H), 3.68 (t, 2H, J=6.0 Hz), 3.38 (t, 2H, J=6.1 Hz), 3.19 (s, 3H), 1.65 (s, 6H), 1.25 (d, 6H, J=6.0 Hz)

Through the synthetic method according to Example 195, compounds from Example 196 to Example 206 were synthesized, and the data of each example are as follows.

TABLE 11 Ex. Compound Analysis data 196 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 711 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), (trifluoromethoxy)phenyl)propan- 10.03 (brs, 1H), 8.29 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 2-yl)phenyl)-5- 7.92 (m, 1H), 7.79 (m, 1H), 7.54 (s, 1H), 7.36 (dd, (((tetrahydrofuran-3- 1H, J = 8.8, 2.1 Hz), 7.06 (m, 1H), 6.78 (s, 1H), 6.74 yl)methyl)sulfonamido)ben- (m, 1H), 6.72 (s, 1H), 4.61~4.67 (m, 1H), 3.84~3.88 zo[b]thiophene-2-carboxamide (m, 1H), 3.58~3.71 (m, 2H), 3.33~3.37 (m, 1H), 3.25~3.28 (m, 2H), 2.56~2.63 (m, 1H), 2.05~2.13 (m, 1H), 1.65 (s, 6H), 1.57~1.64 (m, 1H), 1.25 (d, 6H, J = 6.0 Hz) 197 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 711 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 9.94 (trifluoromethoxy)phenyl)propan- (brs, 1H), 8.28 (s, 1H), 8.00 (d, 1H, J = 9.1 Hz), 7.92 2-yl)phenyl)-5- (s, 1H), 7.79 (s, 1H), 7.54 (s, 1H), 7.35 (d, 1H, (((tetrahydrofuran-2- J = 8.5 Hz), 7.06 (s, 1H), 6.79 (m, 1H), 6.74 (m, 1H), yl)methyl)sulfonamido)ben- 6.72 (s, 1H), 4.62~4.66 (m, 1H), 4.19~4.22 (m, 1H), zo[b]thiophene-2-carboxamide 3.58~3.72 (m, 2H), 3.29~3.30 (m, 2H), 2.02~2.07 (m, 1H), 1.78~1.81 (m, 2H), 1.58~1.65 (m, 7H), 1.25 (d, 6H, J = 5.5 Hz) 198 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 725 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 9.99 (trifluoromethoxy)phenyl)propan- (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.92 2-yl)phenyl)-5- (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.34 (d, 1H, (((tetrahydro-2H-pyran-4- J = 8.3 Hz), 7.06 (s, 1H), 6.79 (s, 1H), 6.74 (s, 1H), yl)methyl)sulfonamido)ben- 6.72 (s, 1H), 4.61~4.67 (m, 1H), 3.80 (d, 2H, zo[b]thiophene-2-carboxamide J = 10.7 Hz), 3.26~3.32 (m, 2H), 3.07 (m, 2H), 2.09~2.13 (m, 1H), 1.75 (m, 1H), 1.71 (m, 1H), 1.65 (s, 6H), 1.22~1.34 (m, 8H) 199 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 722 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.63 (brs, 1H), (trifluoromethoxy)phenyl)propan- 10.55 (s, 1H), 8.22 (s, 1H), 7.95~7.98 (m, 1H), 7.90 2-yl)phenyl)-5-((3,5- (s, 1H), 7.61~7.62 (m, 1H), 7.51 (s, 1H), 7.18~7.20 dimethylisoxazole)-4- (m, 1H), 7.04 (s, 1H), 6.77 (s, 1H), 6.70~6.72 (m, sulfonamido)ben- 2H), 4.61~4.64 (m, 1H), 2.45 (s, 3H), 2.22 (s, 3H), zo[b]thiophene-2-carboxamide 1.63 (s, 6H), 1.23 (d, 6H, J = 5.7 Hz) 200 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 707 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (s, 1H), (trifluoromethoxy)phenyl)propan- 10.29 (brs, 1H), 8.21 (s, 1H), 8.17 (brs, 1H), 7.90 (s, 2-yl)phenyl)-5-((1-methyl- 2H), 7.67 (s, 2H), 7.51 (s, 1H), 7.20~7.24 (m, 1H), 1H-pyrazole)-3- 7.04 (s, 1H), 6.77 (s, 1H), 6.71~6.72 (m, 2H), sulfonamido)ben- 4.60~4.66 (m, 1H), 3.79 (s, 3H), 1.63 (s, 6H), 1.23 zo[b]thiophene-2-carboxamide (d, 6H, J = 5.7 Hz) 201 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 707 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53~10.57 (m, (trifluoromethoxy)phenyl)propan- 2H), 8.22 (s, 1H), 7.91 (s, 2H), 7.82 (s, 1H), 7.70 (s, 2-yl)phenyl)-5-((1-methyl- 1H), 7.53 (s, 1H), 7.26 (d, 1H, J = 8.9 Hz), 7.05 (s, 1H-pyrazole)-4- 1H), 6.79 (s, 1H), 6.72 (m, 2H), 6.62 (s, 1H), sulfonamido)ben- 4.61~4.67 (m, 1H), 3.87 (s, 3H), 1.65 (s, 6H), 1.25 zo[b]thiophene-2-carboxamide (d, 6H, J = 5.7 Hz) 202 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 655 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 9.99 (trifluoromethoxy)phenyl)propan- (brs, 1H), 8.27 (s, 1H), 7.99 (d, 1H, J = 8.4 Hz), 7.92 2-yl)phenyl)-5- (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.36 (d, 1H, (ethylsulfonamido)ben- J = 8.6 Hz), 7.06 (s, 1H), 6.79 (s, 1H), 6.72~6.73 (m, zo[b]thiophene-2-carboxamide 2H), 4.61~4.67 (m, 1H), 3.07~3.13 (m, 2H), 1.65 (s, 6H), 1.19~1.25 (m, 9H) 203 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 669 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.97 (trifluoromethoxy)phenyl)propan- (brs, 1H), 8.25 (s, 1H), 7.96 (d, 1H, J = 8.5 Hz), 7.90 2-yl)phenyl)-5-((1- (s, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.36 (d, 1H, methylethyl)sulfonamido)ben- J = 8.3 Hz), 7.04 (s, 1H), 6.77 (s, 1H), 6.71~6.72 (m, zo[b]thiophene-2-carboxamide 2H), 4.60~4.66 (m, 1H), 3.19~3.27 (m, 1H), 1.64 (s, 6H), 1.23 (d, 12H, J = 5.9 Hz) 204 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 697 (M + 1) isopropoxy-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), (trifluoromethoxy)phenyl)propan- 10.08 (s, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 2-yl)phenyl)-5- 7.90 (s, 1H), 7.81 (s, 1H), 7.53 (s, 1H), 7.36 (d, 1H, ((tetrahydrofuran)-3- J = 8.7 Hz), 7.05 (s, 1H), 6.70~6.78 (m, 3H), sulfonamido)ben- 4.59~4.66 (m, 1H), 3.89~4.00 (m, 2H), 3.77~3.86 zo[b]thiophene-2-carboxamide (m, 2H), 3.59~3.65 (m, 1H), 2.07~2.17 (m, 2H), 1.64 (s, 6H), 1.23 (d, 6H, J = 6.0 Hz) 205 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 759 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): 5 10.55 (s, 1H), (trifluoromethoxy)phenyl)propan- 10.26 (brs, 1H), 8.28 (s, 1H), 8.03 (d, 1H, J = 8.8 Hz), 2-yl)phenyl)-5-((1,1- 7.91 (m, 1H), 7.81 (d, 1H, J = 1.9 Hz), 7.53 (s, 1H), dioxidotetrahydro-2H- 7.38 (dd, 1H, J = 8.7, 2.0 Hz), 7.05 (s, 1H), 6.78 (s, thiopyran)-4- 1H), 6.71~6.72 (m, 2H), 4.63 (m, 1H), 3.51 (m, 1H), sulfonamido)ben- 3.14~3.25 (m, 4H), 2.40~2.42 (m, 2H), 2.04~2.14 zo[b]thiophene-2-carboxamide (m, 2H), 1.64 (s, 6H), 1.24 (d, 6H, J = 6.0 Hz) 206 5-((1-acetylpiperidine)-4- LC/MS ESI (+): 752 (M + 1) sulfonamido)-N-(3-chloro-5- ¹H-NMR(400 MHz, CDCl₃): δ 8.09 (s, 1H), (2-(3-isopropoxy-5- 7.83~7.85 (m, 2H), 7.77 (s, 2H), 7.32 (d, 1H, (trifluoromethoxy)phenyl)propan- J = 8.9 Hz), 7.02 (s, 1H), 6.90 (s, 1H), 6.65 (s, 2H), 2-yl)phenyl)ben- 6.58 (s, 1H), 4.74 (m, 1H), 4.47 (m, 1H), 3.94 (m, zo[b]thiophene-2-carboxamide 1H), 3.26 (m, 1H), 3.05 (m, 1H), 2.54 (m, 1H), 2.12~2.21 (m, 2H), 2.07 (s, 3H), 1.78~1.88 (m, 2H), 1.65 (s, 6H), 1.31 (d, 6H, J = 6.0 Hz)

Example 207 Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(vinylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 195-a was repeated except for using 5-amino-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide (20.0 mg, 0.04 mmol) to obtain N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(vinylsulfonamido)benzo[b]thiophene-2-carboxamide (14.0 mg, 59%).

LC/MS ESI (+): 653 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.55 (s, 1H), 10.16 (brs, 1H), 8.26 (s, 1H), 7.99 (d, 1H, J=8.1 Hz), 7.91 (s, 1H), 7.72 (s, 1H), 7.54 (s, 1H), 7.29 (d, 1H, J=8.6 Hz), 7.05 (s, 1H), 6.81-6.84 (m, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 6.72 (s, 1H), 6.12 (d, 1H, J=16.6 Hz), 6.03 (d, 1H, J=9.4 Hz), 4.62-4.67 (m, 1H), 1.65 (s, 6H), 1.25 (d, 6H, J=5.9 Hz)

Example 208 Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((2-(dimethylamino)ethyl)sulfonamido)benzo[b]thiophene-2-carboxamide

N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(vinylsulfonamido)benzo[b]thiophene-2-carboxamide (Example 207) (10.0 mg, 0.02 mmol) was dissolved in THF (0.5 mL), and 2.0 M solution of NHMe₂ in THF (76.5 μL, 0.15 mmol) was added. The mixture was stirred at room temperature for 17 hours, and the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=20:1) to obtain N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((2-(dimethylamino)ethyl)sulfonamido)benzo[b]thiophene-2-carboxamide (10.0 mg, 93%) as a white solid.

LC/MS ESI (+): 698 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.94 (brs, 1H), 8.27 (s, 1H), 8.00 (d, 1H, J=7.6 Hz), 7.91 (s, 1H), 7.78 (s, 1H), 7.54 (s, 1H), 7.36 (d, 1H, J=6.8 Hz), 7.05 (s, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 6.72 (s, 1H), 4.61-4.67 (m, 1H), 3.22-3.26 (m, 2H), 2.63-2.68 (m, 2H), 2.08 (s, 6H), 1.65 (s, 6H), 1.25 (d, 6H, J=6.0 Hz)

Through the synthetic method according to Example 208, compounds of Example 209 and Example 210 were synthesized, and the data of each example are as follows.

TABLE 12 Ex. Compound Analysis data 209 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 740 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.95 (trifluoromethoxy)phenyl)propan- (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.8 Hz), 7.91 (s, 2-yl)phenyl)-5-((2- 1H), 7.80 (m, 1H), 7.54 (s, 1H), 7.37 (dd, 1H, J = 9.1, morpholinoethyl)sulfon- 1.9 Hz), 7.06 (s, 1H), 6.78 (s, 1H), 6.74 (s, 1H), 6.72 (s, amido)benzo[b]thiophene-2- 1H), 4.61~4.67 (m, 1H), 3.46~3.48 (m, 4H), 3.29~3.30 carboxamide (m, 2H), 2.68~2.72 (m, 2H), 2.29~2.30 (m, 4H), 1.65 (s, 6H), 1.25 (d, 6H, J = 6.0 Hz) 210 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 700 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.54 (s, 1H), 9.98 (trifluoromethoxy)phenyl)propan- (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.6 Hz), 7.96 2-yl)phenyl)-5-((2- (brs, 1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.55 (s, 1H), 7.37 (hydroxy(methyl)amino)ethyl)sulfon- (d, 1H, J = 8.4 Hz), 7.05 (s, 1H), 6.78 (s, 1H), 6.74 (s, amido)benzo[b]thiophene- 1H), 6.72 (s, 1H), 4.61~4.67 (m, 1H), 3.26~3.30 (m, 2-carboxamide 2H), 2.88~2.92 (m, 2H), 2.47 (s, 3H), 1.65 (s, 6H), 1.25 (d, 6H, J = 6.0 Hz)

Example 211 Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(1,1-dioxido-1,2-thiazinan-2-yl)benzo[b]thiophene-2-carboxamide (a) Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((4-chlorobutyl)sulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 195-a was repeated except for using 5-amino-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide (50.0 mg, 0.09 mmol) to obtain N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(4-chlorobutyl)sulfonamido)benzo[b]thiophene-2-carboxamide (46.9 mg, 74%).

LC/MS ESI (+): 717 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 10.57 (s, 1H), 10.00 (s, 1H), 8.29 (s, 1H), 8.03 (d, 1H, J=3.2 Hz), 7.92 (s, 1H), 7.80 (s, 1H), 7.54 (s, 1H), 7.37 (d, 1H, J=8.8 Hz), 7.06 (s, 1H), 6.79 (s, 1H), 6.73 (d, 2H, J=6.0 Hz), 4.63-4.66 (m, 1H), 3.63-3.65 (m, 2H), 3.17-3.20 (m, 2H), 1.81 (m, 4H), 1.65 (s, 6H), 1.25 (d, 6H, J=5.6 Hz)

(b) Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(1,1-dioxido-1,2-thiazinan-2-yl)benzo[b]thiophene-2-carboxamide

N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((4-chlorobutyl)sulfonamido)benzo[b]thiophene-2-carboxamide (43.0 mg, 0.06 mmol), and K₂CO₃ (16.6 mg, 0.12 mmol) were dissolved in anhydrous DMF (1.2 mL), followed by heating at 50° C. for 13 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=20:1) to obtain N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(1,1-dioxido-1,2-thiazinan-2-yl)benzo[b]thiophene-2-carboxamide (33.5 mg, 82%) as a white solid.

LC/MS ESI (+): 681 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.68 (s, 1H), 8.32 (s, 1H), 8.08 (d, 1H, J=8.7 Hz), 7.94 (s, 1H), 7.92 (s, 1H), 7.54 (s, 1H), 7.47 (d, 1H, J=9.0 Hz), 7.07 (s, 1H), 6.79 (s, 1H), 6.73 (m, 2H), 4.61-4.67 (m, 1H), 3.74 (m, 2H), 3.35-3.38 (m, 2H), 2.20 (m, 2H), 1.86 (m, 2H), 1.65 (s, 6H), 1.25 (d, 6H, J=5.8 Hz)

Example 212 Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(1,1-dioxidoisothiazolidin-2-yl)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 211 was repeated except for using 5-amino-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide (50.0 mg, 0.09 mmol) to obtain N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(1,1-dioxidoisothiazolidin-2-yl)benzo[b]thiophene-2-carboxamide (36.0 mg, 68%).

LC/MS ESI (+): 667 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 1H), 8.29 (s, 1H), 8.08 (d, 1H, J=9.0 Hz), 7.91 (s, 1H), 7.74 (s, 1H), 7.54 (s, 1H), 7.48 (d, 1H, J=8.8 Hz), 7.06 (s, 1H), 6.79 (s, 1H), 6.72-6.74 (m, 2H), 4.61-4.67 (m, 1H), 3.85 (m, 2H), 3.57 (m, 2H), 2.44-2.47 (m, 2H), 1.65 (s, 6H), 1.25 (d, 6H, J=5.8 Hz)

Example 213 Synthesis of N-(3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 1-iodo-3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene

1-Bromo-3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene (370.0 mg, 0.85 mmol), NaI (255.0 mg, 1.70 mmol), CuI (8.1 mg, 0.04 mmol), and trans-N,N′-dimethylcyclohexane-1,2-diamine (13.4 μL, 0.09 mmol) were dissolved in 1,4-dioxane (2.0 mL), followed by refluxing at 110° C. overnight. Sat. NaHCO₃ aqueous solution was added to quench the reaction, and the reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 1-iodo-3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene (362.0 mg, 88%) as a yellow liquid.

¹H-NMR (400 MHz, CDCl₃): δ 8.41 (s, 1H), 8.05 (s, 1H), 7.82 (s, 1H), 6.64 (s, 2H), 6.62 (s, 1H), 3.78 (s, 3H), 1.68 (s, 6H)

(b) Synthesis of 3-(2-(3-iodo-5-nitrophenyl)propan-2-yl)-5-(trifluoromethoxy)phenol

The synthesis procedure of Intermediate 41 was repeated except for using 1-iodo-3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene (360.0 mg, 0.75 mmol) to obtain 3-(2-(3-iodo-5-nitrophenyl)propan-2-yl)-5-(trifluoromethoxy)phenol (279.0 mg, 80%).

¹H-NMR (400 MHz, CDCl₃): δ 8.41 (s, 1H), 8.05 (s, 1H), 7.82 (s, 1H), 6.62 (d, 2H, J=6.0 Hz), 6.55 (s, 1H), 5.05 (s, 1H), 1.68 (s, 6H)

(c) Synthesis of 1-iodo-3-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene

The synthesis procedure of Intermediate 42 was repeated except for using 3-(2-(3-iodo-5-nitrophenyl)propan-2-yl)-5-(trifluoromethoxy)phenol (279.0 mg, 0.60 mmol) to obtain 1-iodo-3-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene (286.0 mg, 94%).

¹H-NMR (400 MHz, CDCl₃): δ 8.40 (s, 1H), 8.05 (s, 1H), 7.83 (s, 1H), 6.59-6.61 (m, 3H), 4.45-4.51 (m, 1H), 1.68 (s, 6H), 1.32 (d, 6H, J=6.4 Hz)

(d) Synthesis of 3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)aniline

The synthesis procedure of Intermediate 40 was repeated except for using 1-iodo-3-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-nitrobenzene (260.0 mg, 0.51 mmol) to obtain 3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)aniline (247.0 mg, quant.).

¹H-NMR (400 MHz, CDCl₃): δ 6.97 (s, 1H), 6.88 (s, 1H), 6.63 (s, 2H), 6.56 (s, 1H), 6.39 (s, 1H), 4.45-4.48 (m, 1H), 3.59 (s, 2H), 1.57 (s, 6H), 1.27 (d, 6H, J=6.4 Hz)

(e) Synthesis of N-(3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-Iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)aniline (211.0 mg, 0.43 mmol) to obtain N-(3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (200.0 mg, 64%).

LC/MS ESI (+): 733 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.49 (s, 1H), 9.88 (brs, 1H), 8.28 (s, 1H), 8.20 (s, 1H), 8.03 (d, 1H, J=8.8 Hz), 7.80 (s, 1H), 7.62 (s, 1H), 7.37 (d, 1H, J=8.6 Hz), 7.34 (s, 1H), 6.78 (s, 1H), 6.72 (s, 1H), 6.71 (s, 1H), 4.61-4.67 (m, 1H), 3.02 (s, 3H), 1.63 (s, 6H), 1.25 (d, 6H, J=5.7 Hz)

Example 214 Synthesis of 3-iodo-N-(3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of N-(3-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-(trimethylstannyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

N-(3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (Example 213) (20.0 mg, 0.03 mmol), (SnMe₃)₂ (11.0 mg, 0.03 mmol), and Pd(PPh₃)₄ (3.1 mg, 3.0 μM) were dissolved in toluene (1.0 mL), followed by heating at 105° C. for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain N-(3-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-(trimethylstannyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (19.8 mg, 95%) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ 7.87 (d, 1H, J=7.6 Hz), 7.83 (s, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.65 (s, 1H), 7.40 (s, 1H), 7.28 (d, 1H, J=8.8 Hz), 7.10 (s, 1H), 6.70 (s, 1H), 6.67 (s, 1H), 6.58 (s, 1H), 6.40 (s, 1H), 4.44-4.51 (m, 1H), 3.04 (s, 3H), 1.60 (s, 6H), 1.31 (d, 6H, J=6.0 Hz), 0.28 (t, 9H, J=27.2 Hz)

(b) Synthesis of 3-iodo-N-(3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

N-(3-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-(trimethylstannyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (17.4 mg, 0.02 mmol), NaI (17.2 mg, 0.12 mmol), N-chlorosuccinimide (24.6 mg, 0.18 mmol), and AcOH (5.0 μL) were dissolved in MeOH (0.5 mL), followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂MeOH=20:1) to obtain 3-iodo-N-(3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (1.4 mg, 7%) as a white solid.

¹H-NMR (400 MHz, DMSO-d₆): δ 10.66 (s, 1H), 9.71 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 8.03 (m, 1H), 7.64 (s, 1H), 7.57 (d, 1H, J=8.9 Hz), 7.33 (s, 1H), 6.77 (s, 1H), 6.71 (m, 2H), 4.60-4.66 (m, 1H), 3.05 (s, 3H), 1.63 (s, 6H), 1.24 (d, 6H, J=5.9 Hz)

Example 215 and Example 216 Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide and N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-N-methyl-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide

N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (Example 84) (30.0 mg, 0.05 mmol), CH₃I (8.4 μL, 0.14 mmol), and K₂CO₃ (12.6 mg, 0.09 mmol) were dissolved in anhydrous DMF (1.0 mL), followed by stirring at room temperature for 14 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain white solid compounds of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide (20.2 mg, 66%) and N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-N-methyl-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide (10.6 mg, 34%).

Example 215

LC/MS ESI (+): 673 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 1H), 8.31 (s, 1H), 8.20 (d, 1H, J=7.4 Hz), 8.16 (d, 1H, J=10.5 Hz), 7.90 (m, 1H), 7.53 (s, 1H), 7.07 (m, 1H), 6.79 (s, 1H), 6.74 (m, 1H), 6.72 (s, 1H), 4.61-4.67 (m, 1H), 3.29 (s, 3H), 3.14 (s, 3H), 1.65 (s, 6H), 1.25 (d, 6H, J=6.0 Hz)

Example 216

LC/MS ESI (+): 687 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 7.97 (d, 1H, J=7.4 Hz), 7.92 (d, 1H, J=10.5 Hz), 7.49 (m, 1H), 7.31 (m, 1H), 7.21 (m, 2H), 6.76 (m, 1H), 6.69 (s, 1H), 6.61 (s, 1H), 4.57-4.63 (m, 1H), 3.36 (s, 3H), 3.23 (s, 3H), 3.08 (s, 3H), 1.55 (s, 6H), 1.21 (d, 6H, J=6.0 Hz)

Through the synthetic method according to Examples 215 and 216, compounds from Example 217 to Example 221 were synthesized, and the data of each example are as follows.

TABLE 13 Ex. Compound Analysis data 217 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 772 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.69 (s, 1H), 8.32 (trifluoromethoxy)phenyl)propan- (s, 1H), 8.18 (d, 1H, J = 7.3 Hz), 8.14 (d, 1H, 2-yl)phenyl)-6-fluoro-5-(N- J = 10.2 Hz), 7.90 (m, 1H), 7.53 (s, 1H), 7.07 (m, 1H), (2-morpholinoethyl)methylsulfon- 6.79 (s, 1H), 6.74 (m, 1H), 6.72 (s, 1H), 4.61~4.67 amido)benzo[b]thiophene-2- (m, 1H), 3.75 (m, 2H), 3.42 (m, 4H), 3.19 (s, 3H), carboxamide 2.40~2.43 (m, 2H), 2.30 (m, 4H), 1.65 (s, 6H), 1.25 (d, 6H, J = 6.0 Hz) 218 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 885 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 7.97~7.99 (m, (trifluoromethoxy)phenyl)propan- 1H), 7.92 (d, 1H, J = 10.3 Hz), 7.54 (s, 1H), 7.38 (s, 2-yl)phenyl)-6-fluoro-N-(2- 1H), 7.16 (s, 1H), 7.04 (s, 1H), 6.71 (s, 2H), 6.59 (s, morpholinoethyl)-5-(N-(2- 1H), 4.59 (m, 1H), 3.94 (brs, 2H), 3.68 (s, 2H), 3.41 morpholinoethyl)methylsulfon- (m, 8H), 3.13 (s, 3H), 2.34 (s, 4H), 2.25 (s, 8H), 1.50 amido)benzo[b]thiophene-2- (s, 6H), 1.21 (m, 6H) carboxamide 219 N-(3-chloro-5-(2-(3- LC/MS ESI (+): 730 (M + 1) isopropoxy-5- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.70 (s, 1H), 8.31 (trifluoromethoxy)phenyl)propan- (s, 1H), 8.14~8.17 (m, 2H), 7.90 (m, 1H), 7.52 (s, 2-yl)phenyl)-5-(N-(2- 1H), 7.06 (m, 1H), 6.78 (s, 1H), 6.72 (m, 1H), 6.71 (dimethylamino)ethyl)methyl- (s, 1H), 4.60~4.66 (m, 1H), 3.69~3.71 (m, 2H), 3.16 sulfonamido)-6- (s, 3H), 2.29~2.32 (m, 2H), 2.10 (s, 6H), 1.64 (s, fluorobenzo[b]thiophene-2- 6H), 1.23 (d, 6H, J = 6.0 Hz) carboxamide 220 N-(3-chloro-5-(4- LC/MS ESI (+): 521 (M + 1) chlorophenoxy)phenyl)-5-(N- ¹H-NMR(400 MHz, DMSO-d₆); methylmethylsulfonamido)ben- d 10.71 (s, 1H), 8.30 (s, 1H), 8.10 (d, 1H, J = 8.7 Hz), zo[b]thiophene-2-carboxamide 8.03 (d, 1H, J = 2.0 Hz), 7.76 (t, 1H, J = 1.8 Hz), 7.56 (dd, 1H, J = 8.7, 2.1 Hz), 7.51 (d, 2H, J = 8.9 Hz), 7.36 (t, 1H, J = 2.0 Hz), 7.18 (d, 2H, J = 8.9 Hz), 6.93 (t, 1H, J = 2.0 Hz), 3.32 (s, 3H), 2.99 (s, 3H) 221 N-(3-chloro-5-(2-(4- LC/MS ESI (+): 547 (M + 1) chlorophenyl)propan-2- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.65 (s, 1H), 8.32 yl)phenyl)-5-(N- (s, 1H), 8.11 (d, 1H, J = 8.7 Hz), 8.03 (d, 1H, methylmethylsulfonamido)ben- J = 2.0 Hz), 7.89 (t, 1H, J = 1.8 Hz), 7.56 (dd, 1H, zo[b]thiophene-2-carboxamide J = 8.7, 2.1 Hz), 7.51 (s, 1H), 7.38 (d, 2H, J = 8.7 Hz), 7.28 (d, 2H, J = 8.7 Hz), 7.05 (s, 1H), 3.33 (s, 3H), 3.00 (s, 3H), 1.65 (s, 6H)

Example 222 and Example 223 Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide 1,1-dioxide and N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide 1-oxide

N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (Example 68) (10.0 mg, 0.02 mmol), and mCPBA (10.8 mg, 0.05 mmol) were dissolved in CH₂Cl₂ (1.0 mL), followed by stirring at room temperature for 7 hours. The reaction mixture was extracted with CH₂Cl₂, washed with sat. NaHCO₃ aqueous solution and brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain white solid compounds of N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide 1,1-dioxide (1.2 mg, 11%) and N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide 1-oxide (0.7 mg, 7%).

Example 222

LC/MS ESI (+): 673 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.61 (brs, 1H), 10.53 (s, 1H), 8.32 (s, 1H), 7.87 (d, 1H, J=8.3 Hz), 7.81 (m, 1H), 7.50 (m, 1H), 7.39-7.41 (m, 2H), 7.08 (m, 1H), 6.77 (s, 1H), 6.71 (m, 1H), 6.70 (s, 1H), 4.60-4.66 (m, 1H), 3.15 (s, 3H), 1.63 (s, 6H), 1.23 (d, 6H, J=6.0 Hz)

Example 223

LC/MS ESI (+): 657 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 1H), 10.43 (brs, 1H), 8.11 (s, 1H), 7.98 (d, 1H, J=8.2 Hz), 7.84 (m, 1H), 7.57 (m, 1H), 7.44 (s, 1H), 7.36 (dd, 1H, J=8.3, 1.6 Hz), 7.07 (s, 1H), 6.77 (s, 1H), 6.70-6.72 (m, 2H), 4.60-4.66 (m, 1H), 3.12 (s, 3H), 1.63 (s, 6H), 1.23 (d, 6H, J=5.9 Hz)

Example 224 Synthesis of N-(3-(2-(3-cyanophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 3-(3-methoxybenzoyl)benzonitrile

In 3-methoxybenzoyl chloride (540.0 mg, 3.16 mmol) and Pd₂dba₃CHCl₃ (164.0 mg, 0.16 mmol), 0.5 M solution of (3-cyanophenyl)zinc(II) iodide in THF (6.3 mL, 6.30 mmol) was added at 0° C. The mixture was stirred at room temperature for 3 hours, and sat. NH₄Cl aqueous solution (15.0 mL) was added, followed by extracting with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 3-(3-methoxybenzoyl)benzonitrile (450.0 mg, 57%) as a white solid.

¹H-NMR (300 MHz, CDCl₃): δ 8.08 (s, 1H), 8.04 (d, 1H, J=7.8 Hz), 7.87 (d, 1H, J=7.8 Hz), 7.84 (t, 1H, J=7.8 Hz), 7.42 (t, 1H, J=7.8 Hz), 7.34 (s, 1H), 7.28 (d, 1H, J=7.8 Hz), 7.19 (d, 1H, J=8.2 Hz), 3.88 (s, 3H)

(b) Synthesis of 3-(2-(3-methoxyphenyl)propan-2-yl)benzonitrile

3-(3-Methoxybenzoyl)benzonitrile (350.0 mg, 1.47 mmol) was dissolved in dibromoethane (10.0 mL), and PCl₅ (1.5 g, 6.96 mmol) was added. The reaction mixture was stirred at 110° C. for 7 hours, ice water was added, and extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=1:4) to obtain 3-(dichloro(3-methoxyphenyl)methyl)benzonitrile (258.0 mg) as a yellow oil. CH₂Cl₂ (9.0 mL) was cooled to −40° C., and 1.0 M solution of TiCl₄ in CH₂Cl₂ (0.2 mL, 0.17 mmol) and 1.0 M solution of dimethylzinc in n-heptane (2.6 mL, 2.64 mmol) were added. After stirring for 30 minutes, separated 3-(dichloro(3-methoxyphenyl)methyl)benzonitrile (258.0 mg, 0.88 mmol) dissolved in CH₂Cl₂ (2.2 mL) was added at −40° C. After stirring at 0° C. for 2 hours, the reaction mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 3-(2-(3-methoxyphenyl)propan-2-yl)benzonitrile (156.0 mg, 42%) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ 7.53 (s, 1H), 7.43-7.48 (m, 2H), 7.35 (t, 1H, J=7.5 Hz), 7.22 (t, 1H, J=7.6 Hz), 6.74-6.77 (m, 3H), 3.78 (s, 3H), 1.67 (s, 6H)

(c) Synthesis of 3-(2-(3-hydroxyphenyl)propan-2-yl)benzonitrile

3-(2-(3-Methoxyphenyl)propan-2-yl)benzonitrile (156.0 mg, 0.62 mmol) was dissolved in CH₂Cl₂ (6.0 mL), and 1.0 M solution of BBr₃ in CH₂Cl₂ (1.9 mL, 1.86 mmol) was slowly added at 0° C. The reaction mixture was heated to room temperature, followed by stirring for 1 hour, and the reaction mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=4:6) to obtain 3-(2-(3-hydroxyphenyl)propan-2-yl)benzonitrile (90.0 mg, 61%) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ 7.54 (s, 1H), 7.46 (t, 2H, J=7.3 Hz), 7.36 (t, 1H, J=7.5 Hz), 7.17 (t, 1H, J=7.8 Hz), 6.76 (d, 1H, J=7.8 Hz), 6.65-6.70 (m, 2H), 4.78 (s, 1H), 1.66 (s, 6H)

(d) Synthesis of 3-(2-(3-cyanophenyl)propan-2-yl)phenyl trifluoromethanesulfonate

3-(2-(3-Hydroxyphenyl)propan-2-yl)benzonitrile (90.0 mg, 0.38 mmol) was dissolved in CH₂Cl₂ (4.0 mL), and Tf₂O (96.0 μL, 0.57 mmol) was added at 0° C. The reaction mixture was heated to room temperature, followed by stirring for 3 hours, and the reaction mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=4:1) to obtain 3-(2-(3-cyanophenyl)propan-2-yl)phenyl trifluoromethanesulfonate (110.0 mg, 78%) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ 7.48-7.54 (m, 2H), 7.35-7.43 (m, 3H), 7.19 (d, 1H, J=7.9 Hz), 7.14 (d, 1H, J=8.2 Hz), 7.08 (t, 1H, J=2.0 Hz), 1.70 (s, 6H)

(e) Synthesis of 3-(2-(3-aminophenyl)propan-2-yl)benzonitrile

3-(2-(3-Cyanophenyl)propan-2-yl)phenyl trifluoromethanesulfonate (110.0 mg, 0.30 mmol) was dissolved in anhydrous THF (12.0 mL), and Pd₂(dba)₃ (32.0 mg, 0.03 mmol), rac-BINAP (28.0 mg, 0.05 mmol), and benzophenoneimine (60.0 μL, 0.36 mmol) were added. The mixture was refluxed at 100° C. for 5 hours. The reaction mixture was cooled to room temperature. The reaction mixture was extracted with CH₂Cl₂, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was dissolved in anhydrous THF (12.0 mL), and 2 N HCl aqueous solution (1.6 mL, 3.00 mmol) was added. The mixture was stirred at room temperature for 5 hours, and the reaction mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=4:1) to obtain 3-(2-(3-aminophenyl)propan-2-yl)benzonitrile (30.0 mg, 42%) as a yellow oil.

LC/MS ESI (+): 237 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 7.54 (t, 1H, J=1.5 Hz), 7.43-7.48 (m, 2H), 7.34 (t, 1H, J=7.5 Hz), 7.08 (t, 1H, J=7.6 Hz), 6.59 (d, 1H, J=7.7 Hz), 6.54 (d, 1H, J=8.0 Hz), 6.48 (t, 1H, J=2.0 Hz), 3.61 (brs, 2H), 1.64 (s, 6H)

(f) Synthesis of N-(3-(2-(3-cyanophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

5-(Methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (36.0 mg, 0.13 mmol), 3-(2-(3-aminophenyl)propan-2-yl)benzonitrile (30.0 mg, 0.13 mmol), and HATU (53.0 mg, 0.14 mmol) were dissolved in anhydrous DMF (1.3 mL), and DIPEA (44.0 μL, 0.24 mmol) was added. The mixture was stirred at 40° C. for 3 hours, and the reaction mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=95:5) to obtain N-(3-(2-(3-cyanophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (35.0 mg, 56%) as a white solid.

LC/MS ESI (+): 490 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 10.40 (s, 1H), 9.87 (s, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J=9.2 Hz), 7.67-7.78 (m, 4H), 7.59 (s, 1H), 7.47-7.55 (m, 2H), 7.28-7.36 (m, 2H), 7.00 (d, 1H, J=8.4 Hz), 3.00 (s, 3H), 1.66 (s, 6H)

Example 225 Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide (a) Synthesis of 2′,4′-difluoro-[1,1′-biphenyl]-3-amine

3-Bromoaniline (2.0 g, 11.60 mmol), (2,4-difluorophenyl)boronic acid (1.9 g, 12.20 mmol), Pd(PPh₃)₄ (1.3 g, 1.16 mmol) and Na₂CO₃ (3.7 g, 34.90 mmol) were dissolved in a mixture of DME/H₂O (150.0 mL, 4/1 v/v), followed by stirring at 85° C. for 4 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain 2′,4′-difluoro-[1,1′-biphenyl]-3-amine (1.6 g, 67%) as a colorless oil.

LC/MS ESI (+): 206 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 7.36-7.42 (m, 1H), 7.22 (t, 1H, J=7.8 Hz), 6.82-6.96 (m, 3H), 6.81 (d, 1H, J=1.7 Hz), 6.69 (d, 1H, J=8.0 Hz), 3.68 (brs, 2H)

(b) Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide

6-Nitro-1H-indole-2-carboxylic acid (100.0 mg, 0.49 mmol), 2′,4′-difluoro-[1,1′-biphenyl]-3-amine (109.0 mg, 0.53 mmol), EDC (186.0 mg, 0.97 mmol), HOBt (131.0 mg, 0.97 mmol), and DIPEA (422.0 μL, 2.43 mmol) were dissolved in anhydrous DMF (4.0 mL), followed by stirring at 10° C. for 24 hours. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide (110.0 mg, 58%) as a yellow solid.

LC/MS ESI (+): 394 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 12.50 (brs, 1H), 10.70 (s, 1H), 8.38 (s, 1H), 8.02 (d, 1H, J=1.5 Hz), 7.91-7.94 (m, 3H), 7.57-7.65 (m, 2H), 7.51 (t, 1H, J=7.8 Hz), 7.37-7.44 (m, 1H), 7.20-7.31 (m, 2H)

Through the synthetic method according to Example 225, compounds from Example 226 to Example 246 were synthesized, and the data of each example are illustrated as follows.

TABLE 14 Ex. Compound Analysis data 226 6-nitro-N-(2′- LC/MS ESI (+): 426 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.50 (brs, 1H), 10.61 biphenyl]-3-yl)-1H-indole- (brs, 1H), 8.37 (s, 1H), 7.85~7.93 (m, 5H), 7.76 (t, 1H, 2-carboxamide J = 7.4 Hz), 7.64 (t, 1H, J = 7.4 Hz), 7.59 (s, 1H), 7.10~7.47 (m, 2H), 7.09 (d, 1H, J = 7.6 Hz) 227 5-nitro-N-(2′- LC/MS ESI (+): 426 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.50 (s, 1H), 10.61 biphenyl]-3-yl)-1H-indole- (s, 1H), 8.79 (s, 1H), 8.11 (dd, 1H, J = 9.0, 2.3 Hz), 2-carboxamide 7.84~7.91 (m, 3H), 7.76 (t, 2H, J = 7.4 Hz), 7.64 (t, 1H, J = 7.8 Hz), 7.62 (d, 1H, J = 9.2 Hz), 7.44~7.49 (m, 2H), 7.08 (d, 1H, J = 7.6 Hz) 228 3-methyl-5-nitro-N-(2′- LC/MS ESI (+): 440 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.39 (brs, 1H), 10.25 biphenyl]-3-yl)-1H-indole- (s, 1H), 8.67 (d, 1H, J = 2.3 Hz), 8.11 (dd, 1H, J = 9.2, 2-carboxamide 2.3 Hz), 7.85 (d, 1H, J = 7.3 Hz), 7.72~7.87 (m, 3H), 7.64 (d, 1H, J = 6.5 Hz), 7.58 (d, 1H, J = 9.2 Hz), 7.43~7.48 (m, 2H), 7.08 (d, 1H, J = 8.0 Hz), 2.60 (s, 3H) 229 N-(4′-fluoro-2′- LC/MS ESI (+): 446 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 8.83 (s, 1H), 7.75 (dd, biphenyl]-3-yl)-6- 1H, J = 8.1, 2.1 Hz), 7.64 (dd, 1H, J = 8.1, 1.2 Hz), 7.61 (d, nitroindoline-2- 1H, J = 2.1 Hz), 7.56 (s, 1H), 7.22~7.47 (m, 5H), 7.07 (d, carboxamide 1H, J = 7.2 Hz), 4.59~4.70 (m, 2H), 3.71 (dd, 1H, J = 18.3, 10.8 Hz), 3.28 (m, 1H) 230 6-nitro-N-(2′- LC/MS ESI (+): 428 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 8.82 (s, 1H), biphenyl]-3-yl)indoline-2- 7.31~7.78 (m, 9H), 7.23 (s, 1H), 7.10 (d, 1H, J = 2.1 Hz), carboxamide 4.59~4.70 (m, 2H), 3.71 (dd, 1H, J = 17.7, 10.5 Hz), 3.28 (dd, 1H, J = 17.7, 8.1 Hz) 231 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 396 (M + 1) biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 8.85 (s, 1H), 7.76 (dd, nitroindoline-2- 1H, J = 8.1, 1.8 Hz), 7.72 (d, 1H, J = 1.5 Hz), 7.63~7.65 (m, carboxamide 2H), 7.40 (t, 2H, J = 7.8 Hz), 7.29 (s, 1H), 7.24 (s, 1H), 6.87~6.98 (m, 2H), 4.62~4.73 (m, 2H), 3.72 (dd, 1H, J = 17.7, 10.8 Hz), 3.28 (dd, 1H, J = 17.7, 8.4 Hz), 232 6-nitro-N-(2′- LC/MS ESI (+): 444 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.41 (s, 1H), 9.34 (s, biphenyl]-3- 1H), 8.38~8.44 (m, 2H), 7.96~8.00 (m, 2H), 7.86 (d, 1H, yl)benzo[d]thiazole-2- J = 7.2 Hz), 7.65~7.76 (m, 2H), 7.43~7.50 (m, 2H), 7.13 carboxamide (d, 1H, J = 8.1 Hz) 233 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 395 (M + 1) biphenyl]-3-yl)-5-nitro-1H- ¹H-NMR (300 MHz, DMSO-d₆): δ 14.11 (brs, 1H), 11.19 benzo[d]imidazole-2- (s, 1H), 8.56 (s, 1H), 8.22 (dd, 1H, J = 9.0, 2.2 Hz), 8.14 carboxamide (s, 1H), 7.98 (d, 1H, J = 8.0 Hz), 7.84 (d, 1H, J = 9.0 Hz), 7.60 (m, 1H), 7.50 (t, 1H, J = 7.9 Hz), 7.40 (m, 1H), 7.31 (d, 1H, J = 8.1 Hz), 7.24 (dt, 1H, J = 8.6, 2.4 Hz) 234 5-nitro-N-(2′- LC/MS ESI (+): 427 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 14.07 (brs, 1H), 11.19 biphenyl]-3-yl)-1H- (s, 1H), 8.55 (s, 1H), 8.21 (dd, 1H, J = 9.1, 2.2 Hz), benzo[d]imidazole-2- 7.96~8.02 (m, 2H), 7.82~7.87 (m, 2H), 7.75 (t, 1H, carboxamide J = 7.3 Hz), 7.64 (t, 1H, J = 7.4 Hz), 7.43~7.49 (m, 2H), 7.10 (d, 1H, J = 7.6 Hz) 235 N-(4′-fluoro-2′- LC/MS ESI (+): 445 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 14.12 (brs, 1H), 11.27 biphenyl]-3-yl)-5-nitro-1H- (s, 1H), 8.59 (brs, 1H), 8.24 (d, 1H, J = 8.8 Hz), 7.95~8.04 benzo[d]imidazole-2- (m, 2H), 7.75~7.91 (m, 2H), 7.64 (dt, 1H, J = 8.4, 2.3 Hz), carboxamide 7.44~7.54 (m, 2H), 7.10 (d, 1H, J = 7.3 Hz) 236 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 472 (M + 1) biphenyl]-3-yl)-5-methoxy- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.62 (s, 1H), 10.27 6-(methylsulfonamido)-1H- (s, 1H), 8.83 (s, 1H), 7.97 (s, 1H), 7.88 (d, 1H, indole-2-carboxamide J = 8.0 Hz), 7.56~7.64 (m, 1H), 7.47 (t, 1H, J = 8.4 Hz), 7.40~7.44 (m, 2H), 7.36 (s, 1H), 7.19~7.25 (m, 3H), 3.86 (s, 3H), 2.92 (s, 3H) 237 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 459 (M + 1) biphenyl]-3-yl)-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.59 (s, 1H), 9.89 (methylsulfonamido)ben- (brs, 1H), 8.35 (s, 1H), 8.03 (d, 2H, J = 8.8 Hz), 7.81~7.84 zo[b]thiophene-2-carboxamide (m, 2H), 7.20~7.65 (m, 6H), 3.03 (s, 3H) 238 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 443 (M + 1) biphenyl]-3-yl)-5- ¹H-NMR(300 MHz, DMSO-d₆): δ 10.64 (s, 1H), 9.76 (methylsulfonamido)benzo- (brs, 1H), 8.02 (brs, 1H), 7.86 (m, 1H), 7.20~7.76 (m, furan-2-carboxamide 9H), 2.97 (s, 3H) 239 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 433 (M + 1) biphenyl]-3-yl)-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.04 (s, 1H), 10.43 (trifluoromethoxy)-1H- (s, 1H), 7.98 (s, 1H), 7.89 (d, 1H, J = 8.0 Hz), 7.74 (s, indole-2-carboxamide 1H), 7.47~7.65 (m, 4H), 7.36~7.40 (m, 1H), 7.20~7.28 (m, 3H) 240 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 427 (M + 1) biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.40 (s, 1H), 10.54 (methylsulfonyl)-1H- (s, 1H), 8.03 (s, 1H), 7.99 (s, 1H), 7.96 (d, 1H, indole-2-carboxamide J = 8.8 Hz), 7.90 (dd, 1H, J = 8.0, 1.9 Hz), 7.57~7.65 (m, 3H), 7.51 (t, 1H, J = 8.0 Hz), 7.37~7.44 (m, 1H), 7.20~7.30 (m, 2H), 3.21 (s, 3H) 241 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 473 (M + 1) biphenyl]-3-yl)-3-methyl-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.44 (s, 1H), 9.88 (s, (methylsulfonamido)ben- 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.93 (s, 1H), 7.75 (d, 1H, zo[b]thiophene-2-carboxamide J = 8.0 Hz), 7.70 (d, 1H, J = 1.9 Hz), 7.55~7.63 (m, 1H), 7.48 (t, 1H, J = 8.0 Hz), 7.36~7.43 (m, 2H), 7.29 (d, 1H, J = 7.6 Hz), 7.19~7.26 (m, 1H), 3.01 (s, 3H), 2.58 (s, 3H) 242 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 459 (M + 1) biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.58 (s, 1H), 10.07 (methylsulfonamido)ben- (s, 1H), 8.33 (s, 1H), 7.96~7.98 (m, 2H), 7.80~7.83 (m, zo[b]thiophene-2-carboxamide 2H), 7.56~7.64 (m, 1H), 7.49 (t, 1H, J = 8.0 Hz), 7.36~7.44 (m, 1H), 7.19~7.33 (m, 3H), 3.08 (s, 3H) 243 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 473 (M + 1) biphenyl]-3-yl)-3-methyl-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.44 (s, 1H), 9.88 (s, (methylsulfonamido)ben- 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.93 (s, 1H), 7.75 (d, 1H, zo[b]thiophene-2-carboxamide J = 8.4 Hz), 7.70 (d, 1H, J = 1.9 Hz), 7.55~7.63 (m, 1H), 7.48 (t, 1H, J = 8.0 Hz), 7.35~7.43 (m, 2H), 7.29 (d, 1H, J = 8.0 Hz), 7.19~7.26 (m, 1H), 3.02 (s, 3H), 2.58 (s, 3H) 244 N-(4′-fluoro-2′- LC/MS ESI (+): 444 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.50 (s, 1H), 10.61 biphenyl]-3-yl)-6-nitro-1H- (s, 1H), 8.38 (s, 1H), 7.85~7.97 (m, 4H), 7.88 (dd, 1H, indole-2-carboxamide J = 9.5, 2.7 Hz), 7.61~7.68 (m, 2H), 7.55 (d, 1H, J = 5.7 Hz), 7.48 (t, 1H, J = 7.8 Hz), 7.09 (d, 1H, J = 7.4 Hz) 245 N-(5-acetyl-2′,4′-difluoro- LC/MS ESI (+): 484 (M + 1) [1,1′-biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 10.47 (methylsulfonamido)-1H- (s, 1H), 9.63 (brs, 1H), 8.43 (t, 1H, J = 1.7 Hz), 8.31 (m, indole-2-carboxamide 1H), 7.82 (m, 1H), 7.63~7.74 (m, 2H), 7.40~7.48 (m, 3H), 7.27 (dt, 1H, J = 8.6, 2.4 Hz), 6.99 (dd, 1H, J = 8.6, 2.0 Hz), 2.94 (s, 3H), 2.65 (s, 3H) 246 N-(4-(2,4-difluorophenyl)- LC/MS ESI (+): 482 (M + 1) 1H-indazol-6-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 13.16 (s, 1H), 11.75 (methylsulfonamido)-1H- (s, 1H), 10.36 (s, 1H), 9.61 (brs, 1H), 8.36 (s, 1H), 7.86 indole-2-carboxamide (s, 1H), 7.63~7.75 (m, 2H), 7.41~7.54 (m, 4H), 7.29 (dt, 1H, J = 8.4, 2.7 Hz), 6.99 (dd, 1H, J = 8.6, 1.7 Hz), 2.95 (s, 3H)

Example 247 Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-nitro-1H-indole-2-carboxamide

N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide (266.0 mg, 0.68 mmol) was dissolved in anhydrous DMF (6.0 mL), and K₂CO₃ (207.0 mg, 1.50 mmol) and CH₃I (47.0 μL, 0.75 mmol) were added, followed by stirring at room temperature for 3 hours. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was recrystallized with a mixture of EtOAc/i-Pr₂O/MeOH and filtered to obtain N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-nitro-1H-indole-2-carboxamide (163.0 mg, 59%) as a yellow solid.

LC/MS ESI (+): 408 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 10.70 (s, 1H), 8.63 (s, 1H), 7.92-8.02 (m, 3H), 7.83 (m, 1H), 7.55-7.64 (m, 1H), 7.37-7.52 (m, 3H), 7.21-7.31 (m, 2H), 4.13 (s, 3H)

Example 248 Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 6-amino-N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-1H-indole-2-carboxamide

N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-nitro-1H-indole-2-carboxamide (Example 247) (150.0 mg, 0.37 mmol) was dissolved in a mixture of MeOH/H₂O (4.0 mL, 9/1 v/v), and Zn (242.0 mg, 3.70 mmol) and NH₄Cl (60.0 mg, 1.12 mmol) were added, and ultrasonificated at 40° C. for 2 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, EtOAc:n-Hex=30:70) to obtain 6-amino-N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-1H-indole-2-carboxamide (40.0 mg, 29%) as a gray solid.

LC/MS ESI (+): 378 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 10.13 (s, 1H), 7.98 (s, 1H), 7.79 (d, 1H, J=5.4 Hz), 7.58 (t, 1H, J=2.4 Hz), 7.32-7.45 (m, 3H), 7.20-7.22 (m, 2H), 6.90 (brs, 1H), 6.51 (m, 2H), 5.22 (brs, 2H), 3.85 (s, 3H)

(b) Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-Amino-N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-1H-indole-2-carboxamide (40.0 mg, 0.11 mmol) was dissolved in pyridine (2.0 mL), and methanesulfonyl chloride (9.4 μL, 0.12 mmol) was slowly added at 0° C. The reaction mixture was heated to room temperature, followed by stirring for 15 hours, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, EtOAc:n-Hex=60:40) to obtain N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-(methylsulfonamido)-1H-indole-2-carboxamide (23.4 mg, 47%) as a white solid.

LC/MS ESI (+): 456 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 10.40 (s, 1H), 9.74 (s, 1H), 8.00 (m, 1H), 7.83 (m, 1H), 7.66 (d, 1H, J=8.4 Hz), 7.55-7.61 (m, 1H), 7.33-7.49 (m, 4H), 7.22-7.26 (m, 2H), 7.03 (dd, 1H, J=8.4, 1.5 Hz), 3.97 (s, 3H), 2.99 (s, 3H)

Through the synthetic method according to Examples 247 and 248, compounds from Example 249 to Example 253 were synthesized, and the data of each example are as follows.

TABLE 15 Ex. Compound Analysis data 249 1-methyl-6-nitro-N-(2′- LC/MS ESI (+): 440 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 8.42 (s, 1H), 8.07 (dd, biphenyl]-3-yl)-1H- 1H, J = 9.0, 1.5 Hz), 7.96 (s, 1H), 7.77 (d, 1H, J = 7.4 Hz), indole-2-carboxamide 7.75 (d, 1H, J = 8.8 Hz), 7.70 (d, 1H, J = 8.8 Hz), 7.62 (s, 1H), 7.58 (d, 1H, J = 7.8 Hz), 7.45 (m, 3H), 7.19 (d, 1H, J = 7.3 Hz), 7.08 (s, 1H), 4.18 (s, 3H) 250 1-methyl-5-nitro-N-(2′- LC/MS ESI (+): 440 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 8.66 (d, 1H, J = 1.9 Hz), biphenyl]-3-yl)-1H- 8.25 (dd, 1H, J = 9.2, 2.1 Hz), 7.97 (s, 1H), 7.77 (d, 1H, indole-2-carboxamide J = 7.6 Hz), 7.70 (dd, 1H, J = 8.0, 1.1 Hz), 7.62 (s, 1H), 7.58 (d, 1H, J = 7.8 Hz), 7.45 (m, 4H), 7.18 (m, 2H), 4.14 (s, 3H) 251 3-methyl-1-(2- LC/MS ESI (+): 553 (M + 1) morpholinoethyl)-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.69 (s, 1H), 8.66 (d, nitro-N-(2′- 1H, J = 2.2 Hz), 8.13 (dd, 1H, J = 9.2, 2.2 Hz), 7.78~7.86 (m, (trifluoromethyl)-[1,1′- 5H), 7.63 (t, 1H, J = 7.7 Hz), 7.45 (t, 2H, J = 7.7 Hz), 7.08 (d, biphenyl]-3-yl)-1H- 1H, J = 7.4 Hz), 4.55 (t, 2H, J = 5.5 Hz), 3.38 (t, 4H, J = 4.4 Hz), indole-2-carboxamide 2.56 (t, 2H, y = 5.9 Hz), 2.51 (s, 3H), 2.31 (t, 4H, J = 4.4 Hz) 252 1-(2-morpholinoethyl)-6- LC/MS ESI (+): 539 (M + 1) nitro-N-(2′- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.76 (s, 1H), 8.66 (d, (trifluoromethyl)-[1,1′- 1H, J = 2.2 Hz), 7.98~8.01 (m, 1H), 7.93 (s, 1H), 7.81~7.90 biphenyl]-3-yl)-1H- (m, 4H), 7.78 (t, 1H, J = 7.6 Hz), 7.42~7.48 (m, 2H), 7.33 (s, indole-2-carboxamide 1H), 7.07 (d, 1H, J = 8.4 Hz), 4.80 (t, 2H, J = 5.5 Hz), 3.35 (t, 4H, J = 4.4 Hz), 2.53~2.58 (m, 2H), 2.27~2.36 (m, 4H) 253 1-methyl-6- LC/MS ESI (+): 488 (M + 1) (methylsulfonamido)-N- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.39 (s, 1H), 9.71 (s, (2′-(trifluoromethyl)- 1H), 7.81~7.87 (m, 3H), 7.74 (t, 1H, J = 7.3 Hz), 7.66 (d, 1H, [1,1′-biphenyl]-3-yl)-1H- J = 8.6 Hz), 7.64 (t, 1H, J = 7.4 Hz), 7.40~7.45 (m, 2H), indole-2-carboxamide 7.31~7.34 (m, 2H), 7.01~7.06 (m, 2H), 3.95 (s, 3H), 2.99 (s, 3H)

Example 254 Synthesis of 2-((2-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indol-6-yl)oxy)-2-methylpropanoic acid (a) Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-methoxy-1H-indole-2-carboxamide

6-Methoxy-1H-indole-2-carboxylic acid (69.0 mg, 0.36 mmol), 2′,4′-difluoro-[1,1′-biphenyl]-3-amine (70.0 mg, 0.34 mmol), HATU (155.0 mg, 0.41 mmol), and DIPEA (89.0 μL, 0.51 mmol) were dissolved in anhydrous DMF (1.0 mL), followed by stirring at 40° C. for 12 hours. The reaction mixture was extracted with EtOAc, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=3:1) to obtain N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-methoxy-1H-indole-2-carboxamide (118.0 mg, 92%) as an off-white solid.

LC/MS ESI (+): 379 (M+1)

(b) Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-hydroxy-1H-indole-2-carboxamide

To a solution of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-methoxy-1H-indole-2-carboxamide (118.0 mg, 0.31 mmol) in CH₂Cl₂, 1.0 M solution of BBr₃ in CH₂Cl₂ (3.1 mL, 3.10 mmol) was slowly added at 0° C. The reaction mixture was extracted with EtOAc, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-hydroxy-1H-indole-2-carboxamide (21.0 mg, 19%) as an off-white solid.

LC/MS ESI (+): 365 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.34 (s, 1H), 10.14 (s, 1H), 9.29 (s, 1H), 7.96 (d, 1H, J=1.2 Hz), 7.87 (m, 1H), 7.55-7.64 (m, 1H), 7.33-7.54 (m, 4H), 7.19-7.26 (m, 2H), 6.81 (d, 1H, J=1.8 Hz), 6.60 (dd, 1H, J=8.7, 2.1 Hz)

(c) Synthesis of ethyl 2-((2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indol-6-yl)oxy)-2-methylpropanoate

N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-hydroxy-1H-indole-2-carboxamide (30.0 mg, 0.08 mmol) was dissolved in DMSO (5.0 mL), and KOH (7.0 mg, 0.12 mmol) was added, followed by stirring at room temperature for 10 minutes. Ethyl α-bromoisobutyrate (13.2 μL, 0.09 mmol) was added at room temperature, followed by stirring for 12 hours. The reaction mixture was extracted with EtOAc, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain ethyl 2-((2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indol-6-yl)oxy)-2-methylpropanoate (20.0 mg, 51%) as an off-white solid.

LC/MS ESI (+): 479 (M+1)

(d) Synthesis of 2-((2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indol-6-yl)oxy)-2-methylpropanoic acid

Ethyl 2-((2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indol-6-yl)oxy)-2-methyl propanoate (26.0 mg, 0.05 mmol) was dissolved in a mixture of THF/MeOH/H₂O (4.0 mL, 1/2.4/0.6 v/v), and LiOH.H₂O (3.0 mg, 0.13 mmol) was added. After stirring at room temperature for 12 hours, and after the reaction was complete, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in H₂O (1.0 mL) and acidified to pH 1-2 with 1 N HCl. The precipitate was filtered and dried under reduced pressure to obtain 2-((2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indol-6-yl)oxy)-2-methylpropanoic acid (7.7 mg, 35%) as a white solid.

LC/MS ESI (+): 451 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): 0.3-13.0 (brs, 1H), 11.57 (s, 1H), 10.22 (s, 1H), 7.97 (s, 1H), 7.94 (m, 1H), 7.25-7.63 (m, 5H), 7.19-7.23 (m, 2H), 6.91 (d, 1H, J=2.4 Hz), 6.68 (dd, 1H, J=8.7, 2.4 Hz), 1.53 (s, 6H)

Through the synthetic method according to Example 254, compounds of Example 255 and Example 256 were synthesized, and the data of each example are as follows.

TABLE 16 Ex. Compound Analysis data 255 ethyl 2-((2-((2′,4′- LC/MS ESI (+): 451 (M + 1) difluoro-[1,1′-biphenyl]- ¹H-NMR (300 MHz, DMSO-d₆): δ 9.13 (brs, 1H), 7.80 (d, 3-yl)carbamoyl)-1H- 2H, J = 11.4 Hz), 7.68 (m, 1H), 7.57 (d, 1H, J = 8.7 Hz), indol-6-yl)oxy)acetate 7.41~7.49 (m, 2H), 7.30 (m, 1H), 6.86~6.90 (m, 5H), 4.68 (s, 2H), 4.29 (q, 2H, J = 7.2 Hz), 1.32 (t, 3H, J = 7.2 Hz) 256 2-((2-((2′,4′-difluoro-[1,1′- LC/MS ESI(+): 423 (M + 1) biphenyl]-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 13.13 (brs, 1H), 11.56 yl)carbamoyl)-1H-indol- (brs, 1H), 10.22 (brs, 1H), 7.97 (m, 1H), 7.87 (d, 1H, 6-yl)oxy)acetic acid J = 8.0 Hz), 7.56~7.64 (m, 2H), 7.36~7.49 (m, 3H), 7.20~7.25 (m, 2H), 6.85 (m, 1H), 6.75 (dd, 1H, J = 8.8, 2.3 Hz), 4.68 (s, 2H)

Example 257 Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxamide (a) Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide

6-Nitro-1H-indole-2-carboxylic acid (300.0 mg, 1.46 mmol), 2′,4′-difluoro-[1,1′-biphenyl]-3-amine (328.0 mg, 1.60 mmol), EDC (556.0 mg, 2.91 mmol), HOBt (393.0 mg, 2.91 mmol), and DIPEA (1.3 mL, 7.28 mmol) were dissolved in anhydrous DMF (15.0 mL), followed by stirring at 10° C. for 24 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide (392.0 mg, 69%) as a yellow solid.

LC/MS ESI (+): 394 (M+1)

(b) Synthesis of tert-butyl 2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-6-nitro-1H-indole-1-carboxylate

N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide (392.0 mg, 1.00 mmol), Boc₂O (239.0 mg, 1.10 mmol), and Et₃N (278.0 μL, 1.99 mmol) were dissolved in anhydrous DMF (4.0 mL), followed by stirring at room temperature for 24 hours. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain tert-butyl 2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-6-nitro-1H-indole-1-carboxylate (302.0 mg, 62%) as a yellow solid.

LC/MS ESI (+): 494 (M+1)

(c) Synthesis of tert-butyl 6-amino-2-((2′,4′-difluoro-[1,1-biphenyl]-3-yl)carbamoyl)-1H-indole-1-carboxylate

tert-Butyl 2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-6-nitro-1H-indole-1-carboxylate (302.0 mg, 0.61 mmol), Zn (600.0 mg, 9.18 mmol), and NH₄Cl (164.0 mg, 3.06 mmol) were dissolved in a mixture of MeOH/H₂O (2.5 mL, 4/1 v/v), and ultrasonificated for 2 hours. The reaction mixture was extracted with CH₂Cl₂, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH₂Cl₂:MeOH=99:1) to obtain tert-butyl 6-amino-2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indole-1-carboxylate (218.0 mg, 77%) as a white solid.

LC/MS ESI (+): 464 (M+1)

(d) Synthesis of tert-butyl 2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-6-((N-methylsulfamoyl)amino)-1H-indole-1-carboxylate

tert-Butyl 6-amino-2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indole-1-carboxylate (35.0 mg, 0.08 mmol), and DMAP (32.0 mg, 0.26 mmol) were dissolved in CH₃CN (3.0 mL), and methylsulfamoyl chloride (11.0 mg, 0.08 mmol) was slowly added at 0° C., followed by refluxing at 100° C. for 48 hours. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure to obtain tert-butyl 2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-6-((N-methylsulfamoyl)amino)-1H-indole-1-carboxylate (44.5 mg) as a white solid.

LC/MS ESI (+): 557 (M+1)

(e) Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxamide

Crude tert-butyl 2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-6-((N-methylsulfamoyl)amino)-1H-indole-1-carboxylate (44.5 mg) was dissolved in CH₂Cl₂ (2.0 mL), and TFA (0.5 mL) was slowly added. After stirring at room temperature for 1 hour, 1 N NaOH aqueous solution was added to quench the reaction. The reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH₂Cl₂:MeOH=99:1) to obtain N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxamide (14.3 mg, 2 step yield: 41%) as an off-white solid.

LC/MS ESI (+): 457 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.65 (s, 1H), 10.23 (s, 1H), 9.60 (s, 1H), 7.98 (m, 1H), 7.86-7.89 (m, 1H), 7.56-7.64 (m, 2H), 7.47 (t, 1H, J=7.8 Hz), 7.35-7.43 (m, 3H), 7.19-7.26 (m, 2H), 7.16 (d, 1H, J=5.1 Hz), 6.98 (dd, 1H, J=9.0, 1.7 Hz), 2.47 (d, 3H, J=5.0 Hz)

Through the synthetic method according to Example 257, compounds from Example 258 to Example 279 were synthesized, and the data of each example are as follows.

TABLE 17 Ex. Compound Analysis data 258 5-amino-N-(2′- LC/MS ESI (+): 396 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 9.17 (s, 1H), 7.86 (s, biphenyl]-3-yl)-1H- 1H), 7.70~7.77 (m, 2H), 7.55~7.61 (m, 2H), 7.36~7.51 (m, indole-2-carboxamide 3H), 7.25 (d, 1H, J = 7.4 Hz), 7.13 (d, 1H, J = 7.4 Hz), 6.93 (d, 1H, J = 1.9 Hz), 6.81 (d, 1H, J = 1.5 Hz), 6.78 (dd, 1H, J = 8.6, 2.1 Hz), 3.60 (s, 2H) 259 5-(methylsulfonamido)- LC/MS ESI (+): 474 (M + 1) N-(2′-(trifluoromethyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.80 (s, 1H), 10.30 (s, [1,1′-biphenyl]-3-yl)- 1H), 9.38 (s, 1H), 7.83~7.89 (m, 3H), 7.75 (t, 1H, J = 7.8 Hz), 1H-indole-2- 7.64 (t, 1H, J = 7.8 Hz), 7.52 (d, 1H, J = 1.7 Hz), 7.39~7.47 (m, carboxamide 4H), 7.13 (dd, 1H, J = 8.5, 1.9 Hz), 7.05 (d, 1H, J = 7.6 Hz), 2.90 (s, 3H) 260 6-(methylsulfonamido)- LC/MS ESI (+): 474 (M + 1) N-(2′-(trifluoromethyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 9.35 (s, 1H), 7.87 (s, [1,1′-biphenyl]-3-yl)- 1H), 7.73 (m, 2H), 7.60~7.65 (m, 2H), 7.57 (d, 1H, 1H-indole-2- J = 7.3 Hz), 7.51 (d, 1H, J = 7.6 Hz), 7.41~7.46 (m, 2H), 7.37 carboxamide (d, 1H, J = 7.4 Hz), 7.16 (d, 1H, J = 8.2 Hz), 6.98 (m, 2H), 6.57 (s, 1H), 3.02 (s, 3H) 261 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 444 (M + 1) biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 9.99 (s, 1H), 9.35 (brs, (methylsulfonamido)in- 1H), 7.86 (s, 1H), 7.69 (dd, 1H, J = 7.8, 2.0 Hz), 7.51~7.57 doline-2-carboxamide (m, 1H), 7.33~7.44 (m, 2H), 7.16~7.22 (m, 2H), 6.91 (d, 1H, J = 7.8 Hz), 6.51 (s, 1H), 6.41 (d, 1H, J = 7.8 Hz), 6.21 (s, 1H), 4.37~4.44 (m, 1H), 3.24~3.27 (m, 1H), 2.97~3.06 (m, 1H), 2.89 (s, 3H) 262 N-(4′-fluoro-2′- LC/MS ESI (+): 494 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.00 (s, 1H), 9.35 (brs, biphenyl]-3-yl)-6- 1H), 7.68~7.75 (m, 3H), 7.56~7.60 (m, 1H), 7.34~7.48 (m, (methylsulfonamido)in- 2H), 6.89~7.00 (m, 2H), 6.49 (s, 1H), 6.38~6.42 (m, 1H), doline-2-carboxamide 6.15~6.20 (m, 1H), 4.39~4.43 (m, 1H), 3.24~3.27 (m, 1H), 2.97~3.07 (m, 1H), 2.87 (s, 3H) 263 tert-butyl 6-nitro-2-((2′- LC/MS ESI (+): 526 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.94 (s, 1H), 8.97 (d, biphenyl]-3- 1H, J = 2.1 Hz), 8.20 (dd, 1H, J = 8.8, 2.1 Hz), 7.96 (d, 1H, yl)carbamoyl)-1H- J = 8.6 Hz), 7.83~7.86 (m, 2H), 7.72~7.78 (m, 2H), 7.64 (t, indole-1-carboxylate 1H, J = 7.6 Hz), 7.44 (q, 2H, J = 7.8 Hz), 7.28 (d, 1H, J = 0.8 Hz), 7.07 (d, 1H, J = 7.4 Hz), 1.47 (s, 9H) 264 6-(2,2,2- LC/MS ESI (+): 542 (M + 1) trifluoroethylsulfon- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 10.36 (s, amido)-N-(2′- 1H), 10.28 (s, 1H), 7.84~7.89 (m, 3H), 7.75 (t, 1H, (trifluoromethyl)-[1,1′- J = 7.8 Hz), 7.61~7.67 (m, 2H), 7.42~7.46 (m, 4H), 7.05 (d, biphenyl]-3-yl)-1H- 1H, J = 7.6 Hz), 6.99 (dd, 1H, 7 = 8.4, 1.5 Hz), 4.42 (q, 2H, indole-2-carboxamide J = 9.7 Hz) 265 6-(sulfamoylamino)-N- LC/MS ESI (+): 475 (M + 1) (2′-(trifluoromethyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.63 (s, 1H), 10.21 (s, [1,1′-biphenyl]-3-yl)- 1H), 9.33 (brs, 1H), 7.83~7.88 (m, 3H), 7.72 (t, 1H, 1H-indole-2- J = 7.6 Hz), 7.64 (t, 1H, J = 8.0 Hz), 7.56 (d, 1H, J = 8.8 Hz), carboxamide 7.40~7.47 (m, 2H), 7.33~7.36 (m, 2H), 6.94~6.99 (m, 4H) 266 6-(methylsulfonamido)- LC/MS ESI (+): 474 (M + 1) N-(2′-(trifluoromethyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 9.83 (s, [1,1′-biphenyl]-3-yl)- 1H), 9.59 (s, 1H), 8.27 (d, 1H, J = 2.6 Hz), 8.09 (d, 1H, 1H-indole-3- J = 8.5 Hz), 7.74~7.86 (m, 3H), 7.74 (t, 1H, J = 7.4 Hz), 7.63 carboxamide (t, 1H, J = 7.2 Hz), 7.36~7.46 (m, 3H), 7.03 (dd, 1H, J = 8.5, 1.1 Hz), 6.98 (d, 1H, J = 7.5 Hz), 2.92 (s, 3H) 267 6-((N,N- LC/MS ESI (+): 503 (M + 1) dimethylsulfamoyl)ami- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.64 (s, 1H), 10.22 (s, no)-N-(2′- 1H), 9.82 (s, 1H), 7.81~7.88 (m, 3H), 7.75 (t, 1H, J = 7.6 Hz), (trifluoromethyl)-[1,1′- 7.55~7.66 (m, 2H), 7.45 (dd, 1H, J = 7.4, 2.3 Hz), 7.42 (d, biphenyl]-3-yl)-1H- 1H, J = 8.0 Hz), 7.38 (d, 2H, J = 1.5 Hz), 7.04 (d, 1H, indole-2-carboxamide J = 7.4 Hz), 6.98 (dd, 1H, J = 9.0, 1.9 Hz), 2.69 (s, 6H) 268 N-(2′-(trifluoromethyl)- LC/MS ESI (+): 528 (M + 1) [1,1′-biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.87 (s, 1H), 11.81 (brs, (trifluoromethylsulfon- 1H), 10.34 (s, 1H), 7.83~7.89 (m, 3H), 7.70~7.77 (m, 2H), amido)-1H-indole-2- 7.64 (t, 1H, y = 7.6 Hz), 7.41~7.47 (m, 4H), 7.05 (d, 1H, carboxamide J = 7.6 Hz), 6.98 (dd, 1H, J = 8.6, 1.7 Hz) 269 6-((N- LC/MS ESI (+): 489 (M + 1) methylsulfamoyl)amino)-N- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.65 (s, 1H), 10.21 (s, (2′-(trifluoromethyl)- 1H), 9.57 (brs, 1H), 7.83~7.88 (m, 3H), 7.75 (t, 1H, [1,1′-biphenyl]-3-yl)- J = 7.4 Hz), 7.64 (t, 1H, J = 7.4 Hz), 7.57 (d, 1H, J = 8.6 Hz), 1H-indole-2- 7.34~7.46 (m, 4H), 7.13 (m, 1H), 7.03 (m, 1H), 6.97 (dd, carboxamide 1H, J = 8.6, 1.7 Hz), 2.47 (d, 3H, J = 5.0 Hz) 270 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 442 (M + 1) biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.7 (s, 1H), 10.3 (s, (methylsulfonamido)- 1H), 9.63 (s, 1H), 7.98 (d, 1H, J = 1.5 Hz), 7.88 (dd, 1H, 1H-indole-2- J = 8.2, 1.5 Hz), 7.56~7.74 (m, 2H), 7.48 (t, 1H, 7 = 8.0 Hz), carboxamide 7.36~7.44 (m, 3H), 7.20~7.26 (m, 2H), 6.99 (dd, 1H, J = 8.6, 1.7 Hz), 2.94 (s, 3H) 271 6-amino-N-(2′,4′- LC/MS ESI (+): 364 (M + 1) difluoro-[1,1′-biphenyl]- ¹H-NMR (300 MHz, DMSO-d₆): δ 8.97 (s, 1H), 7.79~7.90 3-yl)-1H-indole-2- (m, 2H), 7.65~7.68 (m, 1H), 7.41~7.49 (m, 3H), 7.28~7.30 carboxamide (m, 1H), 6.89~7.00 (m, 3H), 6.65~6.68 (m, 1H), 6.62 (dd, 1H, J = 8.6, 2.1 Hz), 3.80 (brs, 2H) 272 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 442 (M + 1) biphenyl]-3-yl)-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.81 (s, 1H), 10.33 (s, (methylsulfonamido)- 1H), 9.39 (brs, 1H), 7.98 (d, 1H, J = 1.4 Hz), 7.88 (d, 1H, 1H-indole-2- J = 7.9 Hz), 7.57~7.65 (m, 1H), 7.37~7.52 (m, 5H), carboxamide 7.20~7.28 (m, 2H), 7.13 (dd, 1H, J = 8.8, 2.3 Hz), 2.90 (s, 3H) 273 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 510 (M + 1) biphenyl]-3-yl)-6-(2,2,2- ¹H-NMR (300 MHz, DMSO-d₆); trifluoroethylsulfon- d 11.79 (s, 1H), 10.36 (s, 1H), 10.31 (s, 1H), 7.99 (m, 1H), amido)-1H-indole-2- 7.88 (d, 1H, J = 8.2 Hz), 7.67 (d, 1H, J = 8.8 Hz), 7.56~7.62 carboxamide (m, 1H), 7.48 (t, 1H, J = 8.0 Hz), 7.37~7.44 (m, 3H), 7.20~7.27 (m, 2H), 6.99 (dd, 1H, J = 8.6, 1.9 Hz), 4.42 (q, 2H, J = 9.7 Hz) 274 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 443 (M + 1) biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.65 (s, 1H), 10.24 (s, (sulfamoylamino)-1H- 1H), 9.33 (s, 1H), 7.98 (m, 1H), 7.86~7.89 (m, 1H), indole-2-carboxamide 7.55~7.64 (m, 2H), 7.40~7.50 (m, 2H), 7.34~7.38 (m, 2H), 7.20~7.26 (m, 2H), 6.96~7.00 (m, 3H) 275 N-(2′4′-difluoro-[1,1′- LC/MS ESI (+): 442 (M + 1) biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 9.85 (s, (methylsulfonamido)- 1H), 9.60 (s, 1H), 8.28 (d, 1H, J = 2.4 Hz), 8.11 (d, 1H, 1H-indole-3- J = 8.5 Hz), 7.99 (s, 1H), 7.81 (d, 1H, J = 8.3 Hz), 7.59 (m, carboxamide 1H), 7.36~7.46 (m, 3H), 7.17~7.26 (m, 2H), 7.04 (d, 1H, J = 8.1 Hz), 2.93 (s, 3H) 276 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 471 (M + 1) biphenyl]-3-yl)-6-((N,N- ¹H-NMR (300 MHz, DMSO-d₆); d11.64 (s, 1H), 10.25 (s, dimethylsulfamoyl)ami- 1H), 9.82 (brs, 1H), 7.97 (m, 1H), 7.87 (m, 1H), 7.56~7.64 no)-1H-indole-2- (m, 2H), 7.50 (t, 1H, J = 7.8 Hz), 7.36~7.44 (m, 3H), carboxamide 7.20~7.26 (m, 2H), 6.98 (dd, 1H, J = 8.6, 1.7 Hz), 2.69 (s, 6H) 277 N-(4′-fluoro-2′- LC/MS ESI (+): 492 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 9.29 (s, 1H), 7.86 (s, biphenyl]-3-yl)-6- 1H), 7.61~7.71 (m, 3H), 7.43~7.49 (m, 3H), 7.34~7.41 (m, (methylsulfonamido)- 1H), 7.27~7.31 (m, 1H), 7.12 (d, 1H, J = 7.8 Hz), 6.99~7.00 1H-indole-2- (m, 1H), 6.91 (d, 1H, J = 2.0 Hz), 6.52 (s, 1H), 3.03 (s, 3H) carboxamide 278 6- LC/MS ESI (+): 469 (M + 1) (cyclopropanesulfon- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.72 (s, 1H), 10.95 (s, amido)-N-(4-(2,4- 1H), 9.68 (s, 1H), 8.49 (d, 1H, J = 5.1 Hz), 8.44 (s, 1H), 7.74 difluorophenyl)pyridin- (m, 1H), 7.58~7.62 (m, 2H), 7.42~7.52 (m, 2H), 7.26~7.36 2-yl)-1H-indole-2- (m, 2H), 7.01 (m, 1H), 2.58 (m, 1H), 0.89~0.91 (m, 4H) carboxamide 279 N-(4-(2,4- LC/MS ESI (+): 443 (M + 1) difluorophenyl)pyridin- ¹H-NMR(300 MHz) DMSO-d₆): δ 11.74 (s, 1H), 10.95 (s, 2-yl)-6- 1H), 9.67 (s, 1H), 8.49 (d, 1H, J = 5.1 Hz), 8.44 (s, 1H), (methylsulfonamido)- 7.69~7.77 (m, 1H), 7.60~7.62 (m, 2H), 7.44~7.49 (m, 1H), 1H-indole-2- 7.40 (s, 1H), 7.26~7.35 (m, 2H), 6.96~7.00 (m, 1H), 2.95 carboxamide (s, 3H),

Example 280 Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-N-methyl-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 2′,4′-difluoro-N-methyl-[1,1′-biphenyl]-3-amine

To a mixture of 2′,4′-difluoro-[1,1′-biphenyl]-3-amine (150.0 mg, 0.73 mmol), and triethylorthoformate (3.0 mL), a catalytic amount of TFA was added, followed by refluxing for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in EtOH (2.0 mL). NaBH₄ (276.0 mg, 7.30 mmol) was slowly added at 0° C., followed by refluxing for 2 hours. Water was added to quench the reaction, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=9:1) to obtain 2′,4′-difluoro-N-methyl-[1,1′-biphenyl]-3-amine (140.0 mg, 88%) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ 7.36-7.44 (m, 1H), 7.23-7.28 (m, 1H), 6.82-6.96 (m, 3H), 6.72 (d, 1H, J=1.8 Hz), 6.63 (dd, 1H, J=7.5, 2.4 Hz), 4.02 (brs, 1H), 2.88 (s, 3H)

(b) Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-N-methyl-6-nitro-1H-indole-2-carboxamide

6-Nitro-1H-indole-2-carboxylic acid (51.0 mg, 0.25 mmol), 2′,4′-difluoro-N-methyl-[1,1′-biphenyl]-3-amine (60.0 mg, 0.27 mmol), EDC (58.0 mg, 0.30 mmol), and HOBt (41.0 mg, 0.30 mmol) were dissolved in anhydrous DMF (2.5 mL), and DIPEA (65.0 μL, 0.37 mmol) was added, followed by stirring at room temperature for 24 hours. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-N-methyl-6-nitro-1H-indole-2-carboxamide (30.0 mg, 30%) as a yellow solid.

LC/MS ESI (+): 394 (M+1)

(c) Synthesis of N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-N-methyl-6-(methylsulfonamido)-1H-indole-2-carboxamide

The synthesis procedure of Example 257 was repeated except for using N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-N-methyl-6-nitro-1H-indole-2-carboxamide (45.0 mg, 0.11 mmol) to obtain N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-N-methyl-6-(methylsulfonamido)-1H-indole-2-carboxamide (5.0 mg, 4 step yield: 10%) as a white solid.

LC/MS ESI (+): 456 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.60 (s, 1H), 9.55 (s, 1H), 7.55-7.63 (m, 5H), 7.37-7.43 (m, 2H), 7.33 (m, 1H), 7.25 (d, 1H, J=8.4 Hz), 7.19-7.25 (m, 1H), 6.82 (dd, 1H, J=8.4, 1.8 Hz), 3.42 (s, 3H), 2.89 (s, 3H)

Example 281 Synthesis of N-(5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-amine

(3-Aminophenyl)boronic acid hydrochloride (324.0 mg, 1.87 mmol), and 2-bromo-4-methoxy-1-(trifluoromethyl)benzene (500.0 mg, 1.96 mmol) were dissolved in a mixture of DME/H₂O (25.0 mL, 4/1 v/v), and Pd(PPh₃)₄ (216.0 mg, 0.19 mmol) and Na₂CO₃ (1.2 g, 11.20 mmol) were added, followed by stirring at 85° C. for 2 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain 5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-amine (334.0 mg, 67%) as a colorless oil.

LC/MS ESI (+): 268 (M+1)

(b) Synthesis of N-(5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide

5′-Methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-amine (200.0 mg, 0.75 mmol), 6-nitro-1H-indole-2-carboxylic acid (154.0 mg, 0.75 mmol), and HATU (341.0 mg, 0.90 mmol) were dissolved in anhydrous DMF (3.0 mL), and DIPEA (196.0 μL, 1.12 mmol) was slowed added. After stirring at 18° C. for 3 hours, the reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by column chromatography (n-Hex:EtOAc=2:1) to obtain N-(5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide (320.0 mg, 94%) as a yellow solid.

LC/MS ESI (+): 456 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 12.56 (s, 1H), 10.58 (s, 1H), 8.37 (s, 1H), 7.94 (d, 2H, J=1.3 Hz), 7.84-7.91 (m, 2H), 7.78 (d, 1H, J=8.8 Hz), 7.61 (d, 1H, J=1.1 Hz), 7.46 (t, 1H, J=7.8 Hz), 7.16 (dd, 1H, J=8.2, 2.9 Hz), 7.10 (d, 1H, J=8.2 Hz), 6.94 (d, 1H, J=2.5 Hz), 3.87 (s, 3H)

(c) Synthesis of tert-butyl 2-((5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)carbamoyl)-6-nitro-1H-indole-1-carboxylate

N-(5′-methoxy-T-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide (320.0 mg, 0.70 mmol), Boc₂O (169.0 mg, 0.77 mmol), and Et₃N (294.0 μL, 2.11 mmol) were dissolved in anhydrous DMF (4.0 mL), followed by stirring at 17° C. for 24 hours. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain tert-butyl 2-((5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)carbamoyl)-6-nitro-1H-indole-1-carboxylate (163.0 mg, 42%) as a yellow solid.

LC/MS ESI (+): 556 (M+1)

(d) Synthesis of tert-butyl 2-((5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)carbamoyl)-6-(methylsulfonamido)-1H-indole-1-carboxylate

tert-Butyl 2-((5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)carbamoyl)-6-nitro-1H-indole-1-carboxylate (163.0 mg, 0.29 mmol) was dissolved in a mixture of MeOH/H₂O (5.0 mL, 9/1 v/v), and Zn (288.0 mg, 4.40 mmol) and NH₄Cl (78.0 mg, 1.47 mmol) were added. The reaction mixture was ultrasonificated for 1 hour, filtered through Celite and concentrated under reduced pressure. The residue was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was dissolved in pyridine (3.0 mL), and methanesulfonyl chloride (25.0 μL, 0.32 mmol) was slowly added at 0° C. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain tert-butyl 2-((5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)carbamoyl)-6-(methylsulfonamido)-1H-indole-1-carboxylate (143.0 mg, 2 step yield: 81%) as a white solid.

LC/MS ESI (+): 604 (M+1)

(e) Synthesis of N-(5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

tert-Butyl 2-((5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)carbamoyl)-6-(methylsulfonamido)-1H-indole-1-carboxylate (143.0 mg, 0.24 mmol) was dissolved in CH₂Cl₂ (2.0 mL), and TFA (0.5 mL) was added at 15° C. After stirring for 1 hour, the reaction was quenched with 1 N NaOH aqueous solution. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain N-(5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (26.0 mg, 22%) as a white solid.

LC/MS ESI (+): 504 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 10.30 (s, 1H), 9.63 (s, 1H), 7.85 (m, 2H), 7.77 (d, 1H, J=9.2 Hz), 7.63 (d, 1H, J=8.6 Hz), 7.39-7.45 (m, 3H), 7.13-7.17 (m, 1H), 7.05 (d, 1H, J=8.0 Hz), 6.98 (dd, 1H, J=8.4, 1.1 Hz), 6.93 (d, 1H, J=2.3 Hz), 3.86 (s, 3H), 2.94 (s, 3H)

Example 282 Synthesis of N-(5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide

Through the synthetic method according to Example 281-b, N-(5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide was synthesized.

LC/MS ESI (+): 456 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 12.56 (s, 1H), 10.58 (s, 1H), 8.37 (s, 1H), 7.94 (d, 2H, J=1.3 Hz), 7.84-7.91 (m, 2H), 7.78 (d, 1H, J=8.8 Hz), 7.61 (d, 1H, J=1.1 Hz), 7.46 (t, 1H, J=7.8 Hz), 7.16 (dd, 1H, J=8.2, 2.9 Hz), 7.10 (d, 1H, J=8.2 Hz), 6.94 (d, 1H, J=2.5 Hz), 3.87 (s, 3H)

Through the synthetic method according to Example 280 or Examples 281 and 282, compounds from Example 283 to Example 300 were synthesized, and the data of each example are as follows.

TABLE 18 Ex. Compound Analysis data 283 6-(methylsulfonamido)-N- LC/MS ESI (+): 553 (M + 1) (4′-sulfamoyl-2′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 10.31 (s, (trifluoromethyl)-[1,1′- 1H), 9.64 (s, 1H), 8.26 (s, 1H), 8.15 (d, 1H, J = 7.6 Hz), biphenyl]-3-yl)-1H- 7.88~7.93 (m, 2H), 7.62~7.71 (m, 4H), 7.48 (t, 1H, indole-2-carboxamide J = 8.0 Hz), 7.38~7.42 (m, 2H), 7.07 (d, 1H, J = 8.4 Hz), 6.98 (dd, 1H, J = 8.4, 1.9 Hz), 2.94 (s, 3H) 284 N-(4′-cyano-2′- LC/MS ESI (+): 499 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 10.32 (s, biphenyl]-3-yl)-6- 1H), 9.66 (brs, 1H), 8.43 (s, 1H), 8.23 (d, 1H, J = 7.7 Hz), (methylsulfonamido)-1H- 7.87~7.91 (m, 2H), 7.68 (d, 1H, J = 8.8 Hz), 7.63 (d, 1H, indole-2-carboxamide J = 8.5 Hz), 7.47 (t, 1H, J = 7.7 Hz), 7.39 (d, 2H, J = 6.3 Hz), 7.06 (d, 1H, J = 7.7 Hz), 6.98 (dd, 1H, J = 8.5, 1.8 Hz), 2.94 (s, 3H) 285 6-(methylsulfonamido)-N- LC/MS ESI (+): 519 (M + 1) (4′-nitro-2′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 10.33 (s, (trifluoromethyl)-[1,1′- 1H), 9.62 (brs, 1H), 8.54~8.60 (m, 2H), 7.90~7.94 (m, biphenyl]-3-yl)-1H- 2H), 7.78 (d, 1H, J = 8.8 Hz), 7.63 (d, 1H, J = 8.4 Hz), indole-2-carboxamide 7.50 (t, 1H, J = 8.8 Hz), 7.38~7.40 (m, 2H), 7.10 (d, 1H, J = 8.8 Hz), 6.98 (dd, 1H, J = 8.8, 1.5 Hz), 2.93 (s, 3H) 286 methyl 3′-(6-nitro-1H- LC/MS ESI (+): 484 (M + 1) indole-2-carboxamido)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.56 (s, 1H), 10.62 (s, (trifluoromethyl)-[1,1′- 1H), 8.37 (s, 1H), 8.17~8.20 (m, 1H), 8.05 (d, 1H, biphenyl]-3-carboxylate J = 8.2 Hz), 7.87~7.94 (m, 5H), 7.61 (m, 1H), 7.51 (t, 1H, J = 7.8 Hz), 7.14 (d, 1H, J = 7.8 Hz), 3.91 (s, 3H) 287 methyl 3′-(6- LC/MS ESI (+): 532 (M + 1) (methylsulfonamido)-1H- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 10.30 (s, indole-2-carboxamido)-6- 1H), 9.63 (s, 1H), 8.18 (d, 1H, J = 8.8 Hz), 8.05 (d, 1H, (trifluoromethyl)-[1,1′- J = 8.0 Hz), 7.86~7.92 (m, 3H), 7.63 (d, 1H, J = 8.6 Hz), biphenyl]-3-carboxylate 7.47 (t, 1H, J = 7.8 Hz), 7.37~7.41 (m, 2H), 7.09 (d, 1H, J = 7.8 Hz), 6.98 (dd, 1H, J = 8.4, 1.9 Hz), 3.91 (s, 3H), 2.94 (s, 3H) 288 methyl 4-methoxy-3′-(6- LC/MS ESI (+): 514 (M + 1) nitro-1H-indole-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.56 (s, 1H), 10.59 (s, carboxamido)-6- 1H), 8.37 (s, 1H), 7.89~7.96 (m, 3H), 7.82 (m, 1H), (trifluoromethyl)-[1,1′- 7.59~7.65 (m, 2H), 7.44~7.53 (m, 2H), 7.07~7.11 (m, biphenyl]-3-carboxylate 1H), 3.98 (s, 3H), 3.82 (s, 3H) 289 methyl 4-methoxy-3′-(6- LC/MS ESI (+): 562 (M + 1) (methylsulfonamido)-1H- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.72 (s, 1H), 10.27 (s, indole-2-carboxamido)-6- 1H), 9.64 (s, 1H), 7.88 (dd, 1H, J = 8.0, 1.1 Hz), 7.81 (s, (trifluoromethyl)-[1,1′- 1H), 7.62~7.64 (m, 2H), 7.51 (s, 1H), 7.39~7.46 (m, 3H), biphenyl]-3-carboxylate 7.04 (d, 1H, J = 7.6 Hz), 6.98 (dd, 1H, J = 8.6, 1.9 Hz), 3.98 (s, 3H), 3.82 (s, 3H), 2.94 (s, 3H) 290 6-(methylsulfonamido)-N- LC/MS ESI (+): 475 (M + 1) (3-(3- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 10.29 (s, (trifluoromethyl)pyridin- 1H), 9.63 (brs, 1H), 8.93 (d, 1H, J = 5.7 Hz), 8.33 (dd, 1H, 2-yl)phenyl)-1H-indole-2- J = 7.6, 1.5 Hz), 7.99 (s, 1H), 7.92 (d, 1H, J = 8.8 Hz), carboxamide 7.68~7.71 (m, 1H), 7.63 (d, 1H, J = 8.4 Hz), 7.37~7.50 (m, 3H), 7.16~7.19 (m, 1H), 6.98 (dd, 1H, J = 8.4, 1.5 Hz), 2.94 (s, 3H) 291 6-(methylsulfonamido)-N- LC/MS ESI (+): 475 (M + 1) (3-(4- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.75 (s, 1H), 10.33 (s, (trifluoromethyl)pyridm- 1H), 9.66 (s, 1H), 8.90 (d, 1H, J = 5.9 Hz), 8.74 (s, 1H), 3-yl)phenyl)-1H-indole-2- 7.88~7.94 (m, 3H), 7.64 (d, 1H, J = 8.5 Hz), 7.49 (t, 1H, carboxamide J = 7.7 Hz), 7.40 (dd, 2H, J = 8.5, 1.1 Hz), 7.72 (d, 1H, J = 7.7 Hz), 6.98 (dd, 1H, J = 8.5, 1.8 Hz), 2.94 (s, 3H) 292 6-nitro-N-(3-(2- LC/MS ESI (+): 427 (M + 1) (trifluoromethyl)pyridin- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.54 (s, 1H), 10.63 (s, 3-yl)phenyl)-1H-indole-2- 1H), 8.81 (d, 1H, J = 4.6 Hz), 8.37 (s, 1H), 7.80~8.02 (m, carboxamide 5H), 7.82 (dd, 1H, J = 7.6, 4.6 Hz), 7.62 (s, 1H), 7.52 (t, 1H, J = 8.0 Hz), 7.14 (d, 1H, J = 7.6 Hz) 293 6-(methylsulfonamido)-N- LC/MS ESI (+): 475 (M + 1) (3-(2- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.75 (s, 1H), 10.32 (s, (trifluoromethyl)pyridin- 1H), 9.66 (brs, 1H), 8.80 (d, 1H, J = 5.5 Hz), 7.98 (d, 1H, 3-yl)phenyl)-1H-indole-2- J = 7.7 Hz), 7.89~7.91 (m, 2H), 7.81 (dd, 1H, J = 7.7, carboxamide 4.8 Hz), 7.63 (d, 1H, J = 8.5 Hz), 7.48 (t, 1H, J = 7.7 Hz), 7.40 (d, 2H, J = 8.1 Hz), 7.09 (d, 1H, J = 7.4 Hz), 6.98 (dd, 1H, J = 8.5, 1.8 Hz), 2.50 (s, 3H) 294 N-(3-(6-chloro-4- LC/MS ESI (+): 509 (M + 1) (trifluoromethyl)pyridin- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 10.33 (s, 3-yl)phenyl)-6- 1H), 9.64 (brs, 1H), 8.59 (s, 1H), 8.08 (s, 1H), (methylsulfonamido)-1H- 7.90~7.93 (m, 2H), 7.63 (d, 1H, J = 8.8 Hz), 7.50 (t, 1H, J = 8.4 Hz), indole-2-carboxamide 7.39 (d, 2H, J = 6.5 Hz), 7.11 (d, 1H, J = 8.0 Hz), 6.98 (dd, 1H, J = 8.4, 1.9 Hz), 2.94 (s, 3H) 295 N-(2′-fluoro-4′-methoxy- LC/MS ESI (+): 406 (M + 1) [1,1′-biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.57 (s, 1H), 10.60 (s, nitro-1H-indole-2- 1H), 8.38 (s, 1H), 8.00 (s, 1H), 7.95 (s, 2H), 7.90 (d, 1H, carboxamide J = 9.0 Hz), 7.64 (s, 1H), 7.49 (t, 1H, J = 8.1 Hz), 7.25~7.36 (m, 2H), 6.98~7.07 (m, 2H), 3.82 (s, 3H) 296 tert-butyl 2-((2′-fluoro-4′- LC/MS ESI (+): 554 (M + 1) methoxy-[1,1′-biphenyl]- ¹H-NMR (300 MHz, CDCl₃): δ 8.08 (s, 1H), 7.93 (s, 1H), 3-yl)carbamoyl)-6- 7.77 (brs, 2H), 7.57 (d, 1H, J = 8.4 Hz), 7.44 (t, 1H, (methylsulfonamido)-1H- J = 8.4 Hz), 7.15~7.39 (m, 2H), 7.05 (t, 1H, J = 9.6 Hz), indole-1-carboxylate 6.97 (s, 2H), 6.85 (s, 1H), 6.45 (s, 1H), 3.83 (s, 3H), 3.04 (s, 3H), 1.30 (s, 9H) 297 N-(4-(2-fluoro-5- LC/MS ESI (+): 407 (M + 1) methoxyphenyl)pyridin-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.58 (s, 1H), 11.32 (s, yl)-6-nitro-1H-indole-2- 1H), 8.52 (d, 1H, J = 5.1 Hz) 8.47 (s, 1H), 8.38 (s, 1H), carboxamide 7.92 (s, 2H), 7.82 (s, 1H), 7.42 (d, 1H, J = 5.1 Hz), 7.31 (t, 1H, J = 9.0 Hz), 7.06~7.18 (m, 2H), 3.82 (s, 3H) 298 methyl 6-chloro-3′-(6- LC/MS ESI (+): 450 (M + 1) nitro-1H-indole-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.57 (s, 1H), 10.63 (s, carboxamido)-[1,1′- 1H), 8.37 (s, 1H), 7.93~8.00 (m, 6H), 7.77 (d, 1H, biphenyl]-3-carboxylate J = 8.1 Hz), 7.62 (s, 1H), 7.51 (t, 1H, J = 8.1 Hz), 7.26 (d, 1H, J = 7.8 Hz), 3.88 (s, 3H) 299 methyl 6-chloro-3′-(6- LC/MS ESI (+): 498 (M + 1) (methylsulfonamido)-1H- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 10.31 (s, indole-2-carboxamido)- 1H), 9.64 (s, 1H), 7.90~8.00 (m, 4H), 7.76 (d, 1H, [1,1′-biphenyl]-3- J = 8.4 Hz), 7.62 (d, 1H, J = 8.4 Hz), 7.46 (t, 1H, J = 8.7 Hz), carboxylate 7.39 (d, 2H, J = 4.8 Hz), 7.20 (d, 1H, J = 8.1 Hz), 6.97 (dd, 1H, J = 8.7, 1.8 Hz), 3.88 (s, 3H), 2.94 (s, 3H) 300 methyl 4-chloro-3-(2-(6- LC/MS ESI (+): 499 (M + 1) (methylsulfonamido)-1H- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.75 (s, 1H), 11.01 (s, indole-2- 1H), 9.68 (s, 1H), 8.51 (d, 1H, J = 5.1 Hz), 8.36 (s, 1H), carboxamido)pyridin-4- 8.03 (dd, 1H, J = 8.4, 2.1 Hz), 8.00 (d, 1H, J = 2.1 Hz), yl)benzoate 7.81 (d, 1H, J = 8.4 Hz), 7.63 (d, 1H, J = 2.1 Hz), 7.60 (d, 1H, J = 9.0 Hz), 7.39 (s, 1H), 7.29 (dd, 1H, J = 5.1, 1.5 Hz), 6.97 (d, 1H, J = 8.4 Hz), 3.89 (s, 3H), 2.95 (s, 3H)

Example 301 Synthesis of N-(5-cyano-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 2′,4′-difluoro-5-nitro-[1,1′-biphenyl]-3-carbonitrile

3-Bromo-5-nitrobenzonitrile (200.0 mg, 0.89 mmol), (2,4-difluorophenyl)boronic acid (167.0 mg, 1.06 mmol), Pd(PPh₃)₄ (102.0 mg, 0.09 mmol) and Na₂CO₃ (280.0 mg, 2.64 mmol) were added to a mixture of DME/H₂O (9.0 mL, 4/1 v/v), followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 2′,4′-difluoro-5-nitro-[1,1′-biphenyl]-3-carbonitrile (187.0 mg, 82%) as a white solid.

¹H-NMR (300 MHz, CDCl₃): δ 8.60 (s, 1H), 8.52 (s, 1H), 8.13 (s, 1H), 7.44-7.52 (m, 1H), 6.99-7.11 (m, 2H)

(b) Synthesis of 5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-carbonitrile

2′,4′-Difluoro-5-nitro-[1,1′-biphenyl]-3-carbonitrile (184.0 mg, 0.89 mmol) was dissolved in a mixture of MeOH/H₂O (7.0 mL, 9/1 v/v), and Zn (693.0 mg, 10.60 mmol) and NH₄Cl (189.0 mg, 3.54 mmol) were added. The reaction mixture was ultrasonificated for 2 hours, filtered through Celite and concentrated under reduced pressure. The residue was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=1:1) to obtain 5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-carbonitrile (160.0 mg, 99%) as a colorless oil.

LC/MS ESI (+): 231 (M+1)

(c) Synthesis of N-(5-cyano-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

5-Amino-2′,4′-difluoro-[1,1′-biphenyl]-3-carbonitrile (70.0 mg, 0.28 mmol), 6-(methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (70.0 mg, 0.30 mmol), and HATU (115.0 mg, 0.30 mmol) were dissolved in anhydrous DMF (2.8 mL), and DIPEA (72.0 μL, 0.41 mmol) was slowly added. After stirring at room temperature for 72 hours, the reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=40:1) to obtain N-(5-cyano-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (5.8 mg, 5%) as a white solid.

LC/MS ESI (+): 467 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.80 (s, 1H), 10.57 (s, 1H), 9.67 (s, 1H), 8.35 (s, 1H), 8.23 (s, 1H), 7.75 (s, 1H), 7.65-7.72 (m, 2H), 7.46-7.51 (m, 1H), 7.40-7.43 (m, 2H), 7.28 (td, 1H, J=8.8, 2.3 Hz), 7.00 (dd, 1H, J=8.8, 1.9 Hz), 2.95 (s, 3H)

Through the synthetic method according to Example 301, compounds from Example 302 to Example 336 were synthesized, and the data of each example are as follows.

TABLE 19 Ex. Compound Analysis data 302 N-(5-bromo-2′,4′-difluoro- LC/MS ESI (+): 520 (M + 1) [1,1′-biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), (methylsulfonamido)-1H- 10.40 (s, 1H), 9.65 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H), indole-2-carboxamide 7.60~7.68 (m, 2H), 7.40~7.47 (m, 4H), 7.24 (td, 1H, J = 8.8, 2.3 Hz), 6.99 (dd, 1H, J = 8.8, 1.5 Hz), 2.94 (s, 3H) 303 N-(5-bromo-2′,4′-difluoro- LC/MS ESI (+): 550 (M + 1) [1,1′-biphenyl]-3-yl)-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.64 (s, 1H), methoxy-6- 10.39 (s, 1H), 8.84 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H), (methylsulfonamido)-1H- 7.60~7.68 (m, 1H), 7.36~7.47 (m, 4H), 7.21~7.28 (m, indole-2-carboxamide 2H), 3.86 (s, 3H), 2.93 (s, 3H) 304 N-(5-bromo-2′,4′-difluoro- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.47 (brs, 1H), [1,1′-biphenyl]-3-yl)-6- 10.71 (brs, 1H), 8.20 (s, 1H), 8.04 (s, 1H), 7.96~7.99 (m, 2H), (methylsulfonyl)-1H- 7.58~7.69 (m, 3H), 7.39~7.48 (m, 2H), 7.25 (td, 1H, indole-2-carboxamide J = 9.2, 2.3 Hz), 3.21 (s, 3H) 305 N-(5-bromo-2′,4′-difluoro- LC/MS ESI (+): 537 (M + 1) [1,1′-biphenyl]-3-yl)-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.71 (brs, 1H), (methylsulfonamido)benzo[b]thiophene- 9.93 (brs, 1H), 8.34 (s, 1H), 8.14 (m, 1H), 8.03 (d, 1H, 2-carboxamide J = 8.7 Hz), 7.95 (m, 1H), 7.83 (m, 1H), 7.61~7.69 (m, 1H), 7.36~7.50 (m, 3H), 7.22~7.28 (m, 1H), 3.03 (s, 3H) 306 N-(5-bromo-2′,4′-difluoro- LC/MS ESI (+): 521 (M + 1) [1,1′-biphenyl]-3-yl)-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.79 (brs, 1H), (methylsulfonamido)benzofuran- 9.78 (brs, 1H), 8.17 (m, 1H), 8.00 (s, 1H), 7.79 (s, 1H), 2-carboxamide 7.59~7.72 (m, 3H), 7.26~7.48 (m, 3H), 7.23 (m, 1H), 2.98 (s, 3H) 307 N-(5-bromo-2′,4′-difluoro- LC/MS ESI (+): 535 (M + 1) [1,1′-biphenyl]-3-yl)-6-((N- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.68 (s, 1H), methylsulfamoyl)amino)- 10.37 (s, 1H), 9.60 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 1H-indole-2-carboxamide 7.62~7.68 (m, 1H), 7.58 (d, 1H, J = 8.8 Hz), 7.43~7.46 (m, 2H), 7.36~7.40 (m, 2H), 7.24 (td, 1H, J = 8.4, 2.3 Hz), 7.12 (brs, 1H), 6.98 (dd, 1H, J = 8.8, 1.9 Hz), 2.47 (s, 3H)) 308 N-(5-bromo-2′,4′-difluoro- LC/MS ESI (+): 511 (M + 1) [1,1′-biphenyl]-3-yl)-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.07 (s, 1H), (trifluoromethoxy)-1H- 10.55 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 7.75 (s, 1H), indole-2-carboxamide 7.60~7.68 (m, 1H), 7.56 (d, 1H, J = 8.8 Hz), 7.52 (s, 1H), 7.39~7.46 (m, 2H), 7.21~7.27 (m, 2H) 309 N-(5-bromo-2′,4′-difluoro- LC/MS ESI (+): 551 (M + 1) [1,1′-biphenyl]-3-yl)-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.58 (s, 1H), methyl-6- 9.96 (brs, 1H), 8.07 (s, 1H), 8.01 (d, 1H, J = 8.4 Hz), 7.90 (s, (methylsulfonamido)benzo[b]thiophene- 1H), 7.69 (s, 1H), 7.59~7.67 (m, 1H), 7.48 (s, 1H), 2-carboxamide 7.36~7.46 (m, 2H), 7.20~7.27 (m, 1H), 3.00 (s, 3H), 2.58 (s, 3H) 310 N-(5-bromo-2′,4′-difluoro- LC/MS ESI (+): 537 (M + 1) [1,1′-biphenyl]-3-yl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.70 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 10.09 (s, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.98 (d, 1H, 2-carboxamide J = 8.8 Hz), 7.94 (s, 1H), 7.83 (s, 1H), 7.60~7.68 (m, 1H), 7.39~7.47 (m, 2H), 7.32 (dd, 1H, J = 8.8, 1.9 Hz), 7.21~7.27 (m, 1H), 3.08 (s, 3H) 311 N-(5-bromo-2′,4′-difluoro- LC/MS ESI (+): 551 (M + 1) [1,1′-biphenyl]-3-yl)-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.59 (s, 1H), 9.87 (s, methyl-5- 1H), 8.06 (s, 1H), 8.02 (d, 1H, J = 8.4 Hz), 7.89 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.70 (d, 1H, J = 1.9 Hz), 7.59~7.67 (m, 1H), 7.48 (s, 1H), 2-carboxamide 7.37~7.46 (m, 2H), 7.20~7.26 (m, 1H), 3.02 (s, 3H), 2.58 (s, 3H) 312 6-(methylsulfonamido)-N- LC/MS ESI (+): 460 (M + 1) (2′,4′,5-trifluoro-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.79 (s, 1H), biphenyl]-3-yl)-1H-indole- 10.46 (s, 1H), 9.68 (brs, 1H), 7.86~7.88 (m, 1H), 7.77 (d, 1H, 2-carboxamide J = 1.1 Hz), 7.60~7.71 (m, 2H), 7.38~7.45 (m, 3H), 7.24 (dt, 1H, J = 8.8, 1.9 Hz), 7.12 (d, 1H, J = 9.5 Hz), 7.00 (dd, 1H, J = 8.8, 1.9 Hz), 2.95 (s, 3H) 313 N-(2′,4′-difluoro-5- LC/MS ESI (+): 510 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.77 (s, 1H), biphenyl]-3-yl)-6- 10.57 (s, 1H), 9.68 (s, 1H), 8.32 (s, 1H), 8.27 (s, 1H), (methylsulfonamido)-1H- 7.65~7.74 (m, 2H), 7.57 (s, 1H), 7.41~7.50 (m, 3H), indole-2-carboxamide 7.27 (dt, 1H, J = 8.8, 2.7 Hz), 7.02 (dd, 1H, J = 8.4, 1.9 Hz), 2.95 (s, 3H) 314 N-(2′,4′-difluoro-5- LC/MS ESI (+): 472 (M + 1) methoxy-[1,1′-biphenyl]-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.72 (s, 1H), yl)-6-(methylsulfonamido)- 10.24 (s, 1H), 9.64 (s, 1H), 7.57~7.65 (m, 4H), 7.36~7.43 (m, 1H-indole-2-carboxamide 3H), 7.22 (td, 1H, J = 7.6, 1.9 Hz), 6.99 (dd, 1H, J = 8.8, 1.5 Hz), 6.81 (s, 1H), 3.82 (s, 3H), 2.95 (s, 3H) 315 N-(5-cyano-4′-fluoro-2′- LC/MS ESI (+): 517 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.80 (s, 1H), biphenyl]-3-yl)-6- 10.56 (s, 1H), 9.68 (brs, 1H), 8.35 (s, 1H), 8.07 (s, 1H), (methylsulfonamido)-1H- 7.83 (dd, 1H, J = 9.5, 2.7 Hz), 7.64~7.72 (m, 2H), indole-2-carboxamide 7.55~7.62 (m, 2H), 7.40 (d, 2H, J = 6.1 Hz), 7.00 (dd, 1H, J = 8.4, 1.5 Hz), 2.93 (s, 3H) 316 N-(2′,4′-difluoro-5- LC/MS ESI (+): 503 (M + 1) methoxy-[1,1′-biphenyl]-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.41 (s, 1H), 9.88 (s, yl)-3-methyl-6- 1H), 8.02 (d, 1H, J = 8.4 Hz), 7.70 (d, 1H, J = 2.3 Hz), (methylsulfonamido)benzo[b]thiophene- 7.56~7.64 (m, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 2-carboxamide 7.35~7.42 (m, 2H), 7.18~7.24 (m, 1H), 6.84 (s, 1H), 3.81 (s, 3H), 3.01 (s, 3H), 2.57 (s, 3H) 317 N-(2′,4′-difluoro-5- LC/MS ESI (+): 489 (M + 1) methoxy-[1,1′-biphenyl]-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.55 (s, 1H), yl)-5- 9.90 (brs, 1H), 8.34 (s, 1H), 8.03 (d, 1H, J = 8.8 Hz), 7.81 (s, (methylsulfonamido)benzo[b]thiophene- 1H), 7.52~7.65 (m, 1H), 7.56 (d, 1H, J = 2.3 Hz), 7.52 (d, 2-carboxamide 1H, J = 2.3 Hz), 7.35~7.43 (m, 2H), 7.21 (dt, 1H, J = 8.8, 1.9 Hz), 6.85 (s, 1H), 3.82 (s, 3H), 3.02 (s, 3H) 318 N-(2′,4′-difluoro-5- LC/MS ESI (+): 499 (M + 1) (methylcarbamoyl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.71 (s, 1H), biphenyl]-3-yl)-6- 10.42 (s, 1H), 9.62 (brs, 1H), 8.53~8.56 (m, 1H), 8.31 (s, 1H), (methylsulfonamido)-1H- 8.20 (s, 1H), 7.63~7.72 (m, 3H), 7.39~7.47 (m, 3H), indole-2-carboxamide 7.27 (dt, 1H, J = 8.4, 2.7 Hz), 6.99 (dd, 1H, J = 8.8, 1.9 Hz), 2.95 (s, 3H), 2.81 (d, 3H, J = 4.6 Hz), 319 N-(5-(dimethylcarbamoyl)- LC/MS ESI (+): 513 (M + 1) 2′,4′-difluoro-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), biphenyl]-3-yl)-6- 10.38 (s, 1H), 9.64 (brs, 1H), 8.04 (s, 1H), 7.94 (s, 1H), (methylsulfonamido)-1H- 7.60~7.68 (m, 2H), 7.38~7.45 (m, 3H), 7.21~7.27 (m indole-2-carboxamide 2H), 7.00 (dd, 1H, J = 8.4, 1.5 Hz), 3.00 (s, 6H), 2.95 (s, 3H) 320 N-(2′,4′-difluoro-5- LC/MS ESI (+): 553 (M + 1) (piperidine-1-carbonyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), [1,1′-biphenyl]-3-yl)-6- 10.39 (s, 1H), 9.64 (brs, 1H), 8.04 (s, 1H), 7.94 (s, 1H), (methylsulfonamido)-1H- 7.60~7.68 (m, 2H), 7.37~7.45 (m, 3H), 7.22~7.27 (m indole-2-carboxamide 2H), 7.00 (dd, 1H, J = 8.4, 1.9 Hz), 3.38~3.67 (m, 4H), 2.95 (s, 3H), 1.46~1.70 (m, 6H) 321 N-(2′,4′-difluoro-5- LC/MS ESI (+): 555 (M + 1) (morpholine-4-carbonyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), [1,1′-biphenyl]-3-yl)-6- 10.41 (s, 1H), 9.65 (brs, 1H), 8.07 (s, 1H), 7.97 (s, 1H), (methylsulfonamido)-1H- 7.61~7.70 (m, 2H), 7.39~7.47 (m, 3H), 7.23~7.28 (m indole-2-carboxamide 2H), 7.01 (dd, 1H, J = 8.8, 1.9 Hz), 3.35~3.72 (m, 8H), 2.96 (s, 3H) 322 N-(5-chloro-2′,4′-difluoro- LC/MS ESI (+): 511 (M + 1) [1,1′-biphenyl]-3-yl)-6- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.75 (s, 1H), 9.74 (s, fluoro-5- 1H), 8.34 (s, 1H), 8.10 (d, 1H, J = 10.3 Hz), 7.99~8.02 (m, (methylsulfonamido)benzo[b]thiophene- 2H), 7.90 (s, 1H), 7.65 (m, 1H), 7.42 (m, 1H), 7.36 (s, 2-carboxamide 1H), 7.24 (m, 1H), 3.07 (s, 3H) 323 N-(5-chloro-2′,4′-difluoro- LC/MS ESI (+): 493 (M + 1) [1,1′-biphenyl]-3-yl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 1H), 9.90 (s, (methylsulfonamido)benzo[b]thiophene- 1H), 8.34 (s, 1H), 8.04 (d, 1H, J = 8.7 Hz), 8.00 (s, 1H), 2-carboxamide 7.90 (s, 1H), 7.82 (s, 1H), 7.65 (dd, 1H, J = 15.6, 8.8 Hz), 7.44 (t, 1H, J = 11.1 Hz), 7.36~7.39 (m, 2H), 7.25 (t, 1H, J = 8.3 Hz), 3.03 (s, 3H) 324 N-(5-chloro-3′-methoxy-5′- LC/MS ESI (+): 571 (M + 1) (trifluoromethoxy)-[1,1′- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.72 (s, 1H), 9.90 (s, biphenyl]-3-yl)-5- 1H), 8.34 (s, 1H), 8.03~8.06 (m, 2H), 7.98 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.83 (s, 1H), 7.60 (s, 1H), 7.37 (d, 1H, J = 8.7 Hz), 7.29 (s, 2-carboxamide 1H), 7.22 (s, 1H), 7.02 (s, 1H), 3.80 (s, 3H), 3.03 (s, 3H) 325 N-(5-chloro-3′-methoxy-5′- LC/MS ESI (+): 589 (M + 1) (trifluoromethoxy)-[1,1′- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 1H), 9.79 (s, biphenyl]-3-yl)-6-fluoro-5- 1H), 8.34 (s, 1H), 8.11 (d, 1H, J = 10.3 Hz), 8.01~8.03 (m, (methylsulfonamido)benzo[b]thiophene- 2H), 7.97 (s, 1H), 7.60 (s, 1H), 7.29 (s, 1H), 7.22 (s, 2-carboxamide 1H), 7.02 (s, 1H), 3.89 (s, 3H), 3.07 (s, 3H) 326 N-(5-chloro-3′-methoxy-5′- LC/MS ESI (+): 603 (M + 1) (trifluoromethoxy)-[1,1′- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.86 (s, 1H), 8.36 (s, biphenyl]-3-yl)-6-fluoro-5- 1H), 8.24 (d, 1H, J = 7.6 Hz), 8.17 (d, 1H, J = 10.4 Hz), (N- 8.02 (t, 1H, J = 2.0 Hz), 7.98 (s, 1H), 7.60 (s, 1H), 7.31 (t, methylmethylsulfonamido)benzo[b]thiophene- 1H, J = 2.0 Hz), 7.24 (s, 1H), 7.03 (s, 1H), 3.91 (s, 3H), 2-carboxamide 3.31 (s, 3H), 3.15 (s, 3H) 327 N-(5-chloro-2′,4′-difluoro- LC/MS ESI (+): 549 (M + 1) [1,1′-biphenyl]-3-yl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 1H), ((tetrahydrofuran)-3- 10.10 (s, 1H), 8.34 (s, 1H), 8.05 (d, 1H, J = 8.4 Hz), 8.01 (s, sulfonamido)benzo[b]thiophene- 1H), 7.91 (s, 1H), 7.84 (s, 1H), 7.63~7.69 (m, 1H), 2-carboxamide 7.42~7.48 (m, 1H), 7.38~7.40 (m, 2H), 7.24~7.29 (m, 1H), 3.91~4.02 (m, 2H), 3.80~3.88 (m, 2H), 3.64 (q, 1H, J = 6.4 Hz) 2.13~2.19 (m, 2H) 328 N-(5-chloro-3′-methoxy-5′- LC/MS ESI (+): 627 (M + 1) (trifluoromethoxy)-[1,1′- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.71 (s, 1H), biphenyl]-3-yl)-5- 10.11 (s, 1H), 8.34 (s, 1H), 8.04~8.06 (m, 2H), 7.99 (s, 1H), ((tetrahydrofuran)-3- 7.85 (s, 1H), 7.61 (s, 1H), 7.40 (d, 1H, J = 8.4 Hz), 7.30 (s, sulfonamido)benzo[b]thiophene- 1H), 7.23 (s, 1H), 7.03 (s, 1H), 3.93~4.01 (m, 2H), 2-carboxamide 3.91 (s, 3H), 3.79~3.88 (m, 2H), 3.64 (q, 1H, J = 6.8 Hz) 2.13~2.16 (m, 2H) 329 N-(5-chloro-2′,4′-difluoro- LC/MS ESI (+): 525 (M + 1) [1,1′-biphenyl]-3-yl)-6- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 8.36 (s, fluoro-5-(N- 1H), 8.24 (d, 1H, J = 7.2 Hz), 8.17 (d, 1H, J = 10.4 Hz), methylmethylsulfonamido)benzo[b]thiophene-2- 8.00 (t, 1H, J = 2.0 Hz), 7.91 (s, 1H), 7.59~7.70 (m, 1H), carboxamide 7.45 (td, 1H, J = 10.2, 2.0 Hz), 7.38 (s, 1H), 7.26 (td, 1H, J = 8.0, 2.4 Hz), 3.30 (s, 3H), 3.15 (s, 3H) 330 N-(5-chloro-2′,4′-difluoro- LC/MS ESI (+): 567 (M + 1) [1,1′-biphenyl]-3-yl)-6- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.71 (s, 1H), 9.95 (s, fluoro-5-((tetrahydrofuran)- 1H), 8.27 (s, 1H), 7.97~8.00 (m, 3H), 7.89 (s, 1H), 3- 7.65 (m, 1H), 7.45 (m, 1H), 7.36 (s, 1H), 7.25 (m, 1H), sulfonamido)benzo[b]thiophene- 3.80~3.96 (m, 4H), 3.66 (m, 1H), 2.16~2.18 (m, 2H) 2-carboxamide 331 N-(4-chloro-6-(2,4- LC/MS ESI (+): 494 (M + 1) difluorophenyl)pyridin-2- ¹H-NMR (400 MHz, DMSO-d₆): δ 11.33 (brs, 1H), yl)-5- 9.81 (brs, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 8.02 (m, 1H), (methylsulfonamido)benzo[b]thiophene- 7.96 (d, 1H, J = 8.8 Hz), 7.71 (d, 1H, J = 2.0 Hz), 7.58 (s, 1H), 2-carboxamide 7.40 (m, 1H), 7.31 (dd, 1H, J = 8.8, 2.0 Hz), 7.24 (td, 1H, J = 8.8, 3.0 Hz), 2.94 (s, 3H) 332 N-(3-chloro-5-(thiophen-3- LC/MS ESI (+): 463 (M + 1) yl)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.66 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.91 (brs, 1H), 8.33 (s, 1H), 8.03 (d, 1H, J = 8.7 Hz), 8.01 (s, 2-carboxamide 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.83 (s, 1H), 7.70 (m, 1H), 7.58 (s, 1H), 7.54 (m, 1H), 7.37 (dd, 1H, J = 8.7, 2.0 Hz), 3.02 (s, 3H) 333 6-chloro-N-(5-chloro-2′,4′- LC/MS ESI (+): 527 (M + 1) difluoro-[1,1′-biphenyl]-3- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.81 (s, 1H), 9.65 (s, yl)-5- 1H), 8.36 (s, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 7.98 (s, (methylsulfonamido)benzo[b]thiophene- 1H), 7.89 (s, 1H), 7.65 (dd, 1H, J = 15.4, 8.7 Hz), 7.43 (td, 2-carboxamide 1H, J = 10.2, 2.3 Hz), 7.37 (s, 1H), 7.24 (td, 1H, J = 8.4, 2.3 Hz), 3.07 (s, 3H) 334 N-(3-chloro-5-(1-methyl- LC/MS ESI (+): 460 (M + 1) 1H-pyrrol-2-yl)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.88 (brs, 1H), 8.32 (s, 1H), 8.03 (d, 1H, J = 8.7 Hz), 7.86 (s, 2-carboxamide 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.37 (dd, 1H, J = 8.7, 1.8 Hz), 7.26 (s, 1H), 6.90 (s, 1H), 6.28 (m, 1H), 6.10 (m, 1H), 3.72 (s, 3H), 3.02 (s, 3H) 335 N-(5-chloro-2′,4′-difluoro- LC/MS ESI (+): 509 (M + 1) [1,1′-biphenyl]-3-yl)-3- ¹H-NMR (400 MHz, DMSO-d₆): δ 12.21 (brs, 1H), hydroxy-5- 10.35 (brs, 1H), 9.89 (s, 1H), 7.96 (s, 1H), 7.89~7.91 (m, 2H), (methylsulfonamido)benzo[b]thiophene- 7.81 (s, 1H), 7.65 (dd, 1H, J = 15.6, 8.7 Hz), 2-carboxamide 7.32~7.44 (m, 3H), 7.23 (t, 1H, J = 8.3 Hz), 3.03 (s, 3H) 336 N-(3-chloro-5-(thiophen-2- LC/MS ESI (+): 463 (M + 1) yl)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.67 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.89 (brs, 1H), 8.33 (s, 1H), 8.03 (d, 1H, J = 8.7 Hz), 7.99 (s, 2-carboxamide 1H), 7.91 (s, 1H), 7.82 (s, 1H), 7.61~7.66 (m, 2H), 7.56 (s, 1H), 7.37 (dd, 1H, J = 8.7, 2.1 Hz), 7.18 (m, 1H), 3.02 (s, 3H)

Example 337 Synthesis of N-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 2,6-dichloro-4-(2,4-difluorophenyl)pyridine

The synthesis procedure of Example 301-a was repeated except for using 2,6-dichloro-4-iodopyridine (100.0 mg, 0.37 mmol) to obtain 2,6-dichloro-4-(2,4-difluorophenyl)pyridine (90.0 mg, 95%).

LC/MS ESI (+): 260 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.46 (m, 1H), 7.43 (s, 1H), 7.42 (s, 1H), 6.96-7.06 (m, 2H)

(b) Synthesis of 6-chloro-4-(2,4-difluorophenyl)pyridin-2-amine

2,6-Dichloro-4-(2,4-difluorophenyl)pyridine (70.0 mg, 0.27 mmol), NaN₃ (34.9 mg, 0.54 mmol), Cu₂O (38.4 mg, 0.27 mmol), and L-proline (30.9 mg, 0.27 mmol) were dissolved in DMSO (2.0 mL), followed by stirring at 100° C. for 2 hours. After cooling to room temperature, the reaction mixture was extracted with EtOAc, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=9:1) to obtain 6-chloro-4-(2,4-difluorophenyl)pyridin-2-amine (20.0 mg, 31%).

LC/MS ESI (+): 241 (M+1)

(c) Synthesis of N-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 6-chloro-4-(2,4-difluorophenyl)pyridin-2-amine (5.0 mg, 0.02 mmol) to obtain N-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (520.0 μg, 5%).

LC/MS ESI (+): 494 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.52 (s, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 7.94 (m, 1H), 7.78 (m, 1H), 7.69 (s, 1H), 7.47-7.52 (m, 2H), 7.27-7.32 (m, 2H), 2.93 (s, 3H)

Example 338 Synthesis of N-(3-chloro-5-(pyrazin-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 2-(3-chloro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

1-Bromo-3-chloro-5-nitrobenzene (236.5 mg, 1.00 mmol) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (279.0 mg, 1.10 mmol) were dissolved in anhydrous DMSO (2.0 mL), and Pd(dppf)₂Cl₂.CH₂Cl₂ (40.8 mg, 0.05 mmol) and KOAc (294.0 mg, 3.00 mmol) were added. The reaction mixture was stirred at 120° C. for 30 minutes and cooled to room temperature. After adding water, the reaction mixture was extracted with EtOAc. The organic extract was washed with a saturated NaHCO₃ aqueous solution and brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain 2-(3-chloro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (280.0 mg).

LC/MS ESI (+): 202 (M+1): boronic acid confirmed by mass

(b) Synthesis of 2-(3-chloro-5-nitrophenyl)pyrazine

The synthesis procedure of Example 301-a was repeated except for using crude 2-(3-chloro-5-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (100.0 mg) to obtain 2-(3-chloro-5-nitrophenyl)pyrazine (44.0 mg, 53%).

LC/MS ESI (+): 236 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 9.12 (s, 1H), 8.81 (s, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 8.40 (s, 1H), 8.32 (s, 1H)

(c) Synthesis of 3-chloro-5-(pyrazin-2-yl)aniline

The synthesis procedure of Intermediate 39 was repeated except for using 2-(3-chloro-5-nitrophenyl)pyrazine (44.0 mg, 0.19 mmol) to obtain 3-chloro-5-(pyrazin-2-yl)aniline (35.0 mg, 92%).

LC/MS ESI (+): 206 (M+1)

¹H-NMR (400 MHz, CDCl₃): 6, 8.96 (s, 1H), 8.62 (s, 1H), 8.53 (s, 1H), 7.36 (s, 1H), 7.23 (s, 1H), 6.78 (s, 1H), 3.90 (brs, 2H)

(d) Synthesis of N-(3-chloro-5-(pyrazin-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-chloro-5-(pyrazin-2-yl)aniline (35.0 mg, 0.17 mmol) to obtain N-(3-chloro-5-(pyrazin-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (10.0 mg, 13%).

LC/MS ESI (+): 459 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 1H), 9.85 (brs, 1H), 9.24 (s, 1H), 8.71 (s, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.95 (d, 1H, J=8.8 Hz), 7.93 (s, 1H), 7.73 (s, 1H), 7.29 (d, 1H, J=8.8 Hz), 2.93 (s, 3H)

Through the synthetic method according to Example 338, compounds of Example 339 and Example 340 were synthesized, and the data of each example are as follows.

TABLE 20 Ex. Compound Analysis data 339 N-(3-chloro-5-(6- LC/MS ESI (+): 493 (M + 1) chloropyrazin-2-yl)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.86 (s, 1H), 5- 9.90 (brs, 1H), 9.35 (s, 1H), 8.85 (s, 1H), 8.45 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 8.39 (s, 1H), 8.22 (s, 1H), 8.03~8.06 (m, 2H), 7.83 (s, 1H), 2-carboxamide 7.37 (d, 1H, J = 8.8 Hz), 3.02 (s, 3H) 340 N-(3-chloro-5-(1-methyl- LC/MS ESI (+): 461 (M + 1) 1H-imidazol-5-yl)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.68 (s, 1H), 5- 9.88 (brs, 1H), 8.32 (s, 1H), 8.04 (d, 1H, J = 8.7 Hz), 7.93 (s, (methylsulfonamido)benzo[b]thiophene- 1H), 7.83 (s, 1H), 7.82 (s, 1H), 7.76 (s, 1H), 7.37 (dd, 2-carboxamide 1H, J = 8.7, 1.8 Hz), 7.36 (s, 1H), 7.17 (s, 1H), 3.74 (s, 3H), 3.02 (s, 3H)

Example 341 and Example 342 Synthesis of N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide and N-(5-bromo-2′,4′-difluoro-[1,1-biphenyl]-3-yl)-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide

N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (Example 302) (26.5 mg, 0.05 mmol), MeI (3.8 μL, 0.06 mmol), and K₂CO₃ (10.6 mg, 0.08 mmol) were dissolved in anhydrous DMF (1.0 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=2:1) to obtain white solid compounds of N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide (8.8 mg, 31%) and N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide (16.0 mg, 59%).

Example 341

LC/MS (ESI)+: 548 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 10.58 (s, 1H), 8.16 (s, 1H), 7.98 (s, 1H), 7.73 (d, 1H, J=8.4 Hz), 7.59-7.66 (m, 2H), 7.39-7.46 (m, 3H), 7.26 (dd, 1H, J=8.0, 3.1 Hz), 7.18 (d, 1H, J=8.8 Hz), 4.03 (s, 3H), 3.32 (s, 3H), 2.99 (s, 3H)

Example 342

¹H-NMR (300 MHz, DMSO-d₆): δ 12.34 (s, 1H), 10.47 (s, 1H), 8.08 (s, 1H), 7.94 (s, 1H), 7.60-7.70 (m, 1H), 7.39-7.48 (m, 5H), 7.21-7.30 (m, 2H), 3.30 (s, 3H), 2.95 (s, 3H)

Through the synthetic methods according to Examples 341 and 342, compounds from Example 343 to Example 348 were synthesized, and the data of each example are as follows.

TABLE 21 Ex. Compound Analysis data 343 1-methyl-6-(N- LC/MS ESI (+): 502 (M + 1) methylmethylsulfonamido)- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.47 (s, 1H), N-(2′-(trifluoromethyl)- 7.82~7.87 (m, 3H), 7.73~7.77 (m, 2H), 7.61~7.67 (m, [1,1′-biphenyl]-3-yl)-1H- 2H), 7.40~7.46 (m, 2H), 7.35 (s, 1H), 7.18 (dd, 1H, J = 8.6, indole-2-carboxamide 1.7 Hz), 7.05 (d, 1H, J = 7.8 Hz), 4.01 (s, 3H), 3.31 (s, 3H), 2.99 (s, 3H) 344 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 456 (M + 1) biphenyl]-3-yl)-6-(N- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.90 (s, 1H), 10.37 (s, methylmethylsulfonamido)- 1H), 7.99 (d, 1H, J = 1.5 Hz), 7.89 (d, 1H, J = 8.0 Hz), 1H-indole-2-carboxamide 7.72 (d, 1H, J = 8.4 Hz), 7.57~7.65 (m, 1H), 7.36~7.51 (m, 4H), 7.21~7.28 (m, 2H), 7.16 (dd, 1H, J = 8.4, 1.9 Hz), 3.28 (s, 3H), 2.95 (s, 3H) 345 N-(2′,4′-difluoro-[1,1′- LC/MS ESI (+): 470 (M + 1) biphenyl]-3-yl)-1-methyl-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.47 (s, 1H), 8.02 (d, (N- 1H, J = 1.5 Hz), 7.84 (dd, 1H, J = 8.0, 1.6 Hz), 7.72 (d, 1H, methylmethylsulfonamido)- J = 8.4 Hz), 7.66 (d, 1H, J = 1.5 Hz), 7.50~7.64 (m, 1H), 1H-indole-2-carboxamide 7.40~7.47 (m, 2H), 7.39 (s, 1H), 7.19~7.25 (m, 2H), 7.19 (dd, 1H, J = 8.4, 1.9 Hz), 4.03 (s, 3H), 3.32 (s, 3H), 2.99 (s, 3H) 346 6-(N- LC/MS ESI (+): 488 (M + 1) methylmethylsulfonamido)- ¹H-NMR (300 MHz, CDCl₃ + DMSO-d₆): δ 10.74 (s, 1H), N-(2′-(trifluoromethyl)- 9.46 (s, 1H), 7.83~7.87 (m, 1H), 7.75~7.77 (m, 2H), [1,1′-biphenyl]-3-yl)-1H- 7.67 (d, 1H, J = 8.6 Hz), 7.59 (t, 1H, J = 7.3 Hz), 7.47~7.52 (m, indole-2-carboxamide 2H), 7.36~7.42 (m, 3H), 7.08~7.15 (m, 2H), 3.38 (s, 3H), 2.88 (s, 3H) 347 N-(2′,4′-difluoro-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 12.33 (s, 1H), 10.27 (s, methoxy-[1,1′-biphenyl]-3- 1H), 7.57~7.65 (m, 1H), 7.36~7.51 (m, 6H), yl)-6-(N- 7.19~7.29 (m, 2H), 6.85 (s, 1H), 3.83 (s, 3H), 3.30 (s, 3H), 2.95 (s, methylmethylsulfonamido)- 3H) 1H-indole-2-carboxamide 348 N-(2′,4′-difluoro-5- LC/MS ESI (+): 500 (M + 1) methoxy-[1,1′-biphenyl]-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.43 (s, 1H), 7.71 (d, yl)-1-methyl-6-(N- 1H, J = 9.2 Hz), 7.65 (s, 1H), 7.58~7.65 (m, 2H), 7.53 (s, methylmethylsulfonamido)- 1H), 7.38~7.43 (m, 1H), 7.36 (s, 1H), 7.16~7.22 (m, 2H), 1H-indole-2-carboxamide 6.82 (s, 1H), 4.02 (s, 3H), 3.82 (s, 3H), 3.32 (s, 3H), 2.99 (s, 3H)

Example 349 Synthesis of N-(2′,4′-difluoro-5-(6-fluoropyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-amine

3,5-Dibromoaniline (2.3 g, 9.06 mmol), (2,4-difluorophenyl)boronic acid (1.4 g, 9.06 mmol), Pd(PPh₃)₄ (1.0 g, 0.91 mmol) and Na₂CO₃ (2.9 g, 27.18 mmol) were added to a mixture of DME/H₂O (85.0 mL, 4/1 v/v), followed by stirring at 85° C. for 4 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (1.1 g, 43%) as a yellow solid.

LC/MS ESI (+): 284 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 7.50 (td, 1H, J=8.8, 6.9 Hz), 7.33 (ddd, 1H, J=11.1, 9.5, 2.7 Hz), 7.15 (m, 1H), 6.77 (m, 1H), 6.73 (m, 1H), 6.66 (m, 1H), 5.56 (s, 2H)

(b) Synthesis of 2′,4′-difluoro-5-(6-fluoropyridin-3-yl)-[1,1′-biphenyl]-3-amine

5-Bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (50.0 mg, 0.76 mmol), (6-fluoropyridin-3-yl)boronic acid (50.0 mg, 0.35 mmol), Pd(dppf)Cl₂ (14.0 mg, 0.02 mmol) and K₂CO₃ (49.0 mg, 0.35 mmol) were added to a mixture of DMA/H₂O (2.2 mL, 9/1 v/v). The reaction was performed in a microwave with 100 W, at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature and then extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain 2′,4′-difluoro-5-(6-fluoropyridin-3-yl)-[1,1′-biphenyl]-3-amine (32.0 mg, 61%) as a colorless oil.

LC/MS ESI (+): 301 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 8.42 (m, 1H), 7.97 (td, 1H, J=8.4, 2.5 Hz), 7.44 (m, 1H), 6.89-7.02 (m, 4H), 6.84-6.85 (m, 2H), 3.89 (brs, 2H)

(c) Synthesis of N-(2′,4′-difluoro-5-(6-fluoropyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(Methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (29.0 mg, 0.10 mmol), 2′,4′-difluoro-5-(6-fluoropyridin-3-yl)[1,1′-biphenyl]-3-amine (30.0 mg, 0.10 mmol), and HATU (42.0 mg, 0.11 mmol) were dissolved in anhydrous DMF (2.0 mL), and DIPEA (26.0 μL, 0.15 mmol) was added. The reaction mixture was stirred at 40° C. for 14 hours, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:3) to obtain N-(2′,4′-difluoro-5-(6-fluoropyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (22.0 mg, 40%) as a white solid.

LC/MS ESI (+): 537 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 10.41 (s, 1H), 9.66 (s, 1H), 8.61 (d, 1H, J=1.9 Hz), 8.35 (dt, 1H, J=8.4, 2.7 Hz), 8.17 (m, 1H), 8.08 (m, 1H), 7.76 (m, 1H), 7.66 (d, 1H, J=8.6 Hz), 7.57 (brs, 1H), 7.41-7.48 (m, 3H), 7.35 (dd, 1H, J=8.6, 2.9 Hz), 7.26 (dt, 1H, J=8.6, 2.9 Hz), 6.99 (dd, 1H, J=8.6, 1.5 Hz), 2.95 (s, 3H)

Through the synthetic method according to Example 349, compounds from Example 350 to Example 363 were synthesized, and the data of each example are as follows.

TABLE 22 Ex. Compound Analysis data 350 tert-butyl 2-(2′,4′-difluoro- LC/MS ESI (+): 607 (M + 1) 5-(6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.71 (s, 1H), 10.29 (s, (methylsulfonamido)-1H- 1H), 9.64 (brs, 1H), 7.90~7.94 (m, 2H), 7.59~7.67 (m, 2H), indole-2-carboxamido)- 7.31~7.45 (m, 4H), 7.19~7.27 (m, 2H), 6.98 (dd, 1H, J = 8.8, [1,1′-biphenyl]-3-yl)-1H- 1.9 Hz), 6.36~6.37 (m, 1H), 6.31~6.33 (m, 1H), 2.94 (s, pyrrole-1-carboxylate 3H), 1.30 (s, 9H) 351 N-(2′,4′-difluoro-5-(1H- LC/MS ESI (+): 508 (M + 1) pyrazol-3-yl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 13.02 (brs, 1H), 11.71 (s, biphenyl]-3-yl)-6- 1H), 10.27 (s, 1H), 9.63 (brs, 1H), 8.22~8.24 (m, 1H), (methylsulfonamido)-1H- 8.01~8.04 (m, 1H), 7.91~7.93 (m, 1H), 7.83 (s, 1H), indole-2-carboxamide 7.63~7.76 (m, 2H), 7.48 (s, 1H), 7.35~7.45 (m, 3H), 7.25 (dt, 1H, J = 7.7, 1.8 Hz), 6.98 (dd, 1H, J = 8.5, 1.8 Hz), 2.95 (s, 3H) 352 N-(2′,4′-difluoro-5-(1H- LC/MS ESI (+): 507 (M + 1) pyrrol-2-yl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 11.41 (brs, biphenyl]-3-yl)-6- 1H), 10.27 (s, 1H), 9.64 (brs, 1H), 8.07 (s, 1H), 7.77 (s, (methylsulfonamido)-1H- 1H), 7.63~7.71 (m, 2H), 7.53 (s, 1H), 7.38~7.46 (m, 3H), indole-2-carboxamide 7.26 (dt, 1H, J = 8.4, 2.3 Hz), 7.00 (dd, 1H, J = 8.8, 1.9 Hz), 6.88 (s, 1H), 6.52 (s, 1H), 6.16 (dd, 1H, J = 5.3, 2.3 Hz), 2.95 (s, 3H) 353 N-(2′,4′-difluoro-5-(1- LC/MS ESI (+): 521 (M + 1) methyl-1H-pyrrol-2-yl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.76 (s, 1H), 10.33 (s, [1,1′-biphenyl]-3-yl)-6- 1H), 9.65 (brs, 1H), 7.98 (s, 1H), 7.91 (s, 1H), (methylsulfonamido)-1H- 7.63~7.71 (m, 2H), 7.38~7.45 (m, 3H), 7.29 (d, 1H, J = 1.5 Hz), indole-2-carboxamide 7.24 (dt, 1H, J = 9.6, 2.6 Hz), 6.99 (dd, 1H, J = 8.5, 1.8 Hz), 6.89 (t, 1H, J = 2.6 Hz), 6.27 (dd, 1H, J = 3.7, 1.8 Hz), 6.10 (dd, 1H, J = 3.7, 2.6 Hz), 3.74 (s, 3H), 2.94 (s, 3H) 354 N-(2′,4′-difluoro-5- LC/MS ESI (+): 524 (M + 1) (thiophen-2-yl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 10.37 (s, biphenyl]-3-yl)-6- 1H), 9.64 (brs, 1H), 8.19 (s, 1H), 7.97 (s, 1H), (methylsulfonamido)-1H- 7.53~7.74 (m, 5H), 7.39~7.47 (m, 3H), 7.26 (dt, 1H, J = 8.8, 1.9 Hz), indole-2-carboxamide 7.19 (dd, 1H, J = 5.3, 3.8 Hz), 7.00 (dd, 1H, J = 8.4, 1.9 Hz), 2.95 (s, 3H) 355 N-(2′,4′-difluoro-5- LC/MS ESI (+): 524 (M + 1) (thiophen-3-yl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.75 (s, 1H), 10.35 (s, biphenyl]-3-yl)-6- 1H), 9.66 (brs, 1H), 8.16 (s, 1H), 7.95 (d, 1H, J = 1.5 Hz), (methylsulfonamido)-1H- 7.92 (dd, 1H, J = 3.1, 1.5 Hz), 7.64~7.74 (m, 3H), indole-2-carboxamide 7.57~7.58 (m, 2H), 7.39~7.47 (m, 3H), 7.25 (dt, 1H, J = 8.8, 1.9 Hz), 7.00 (dd, 1H, J = 8.4, 1.9 Hz), 2.95 (s, 3H) 356 N-(2′,4′-difluoro-5- LC/MS ESI (+): 519 (M + 1) (pyridin-4-yl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 10.44 (s, biphenyl]-3-yl)-6- 1H), 9.56 (brs, 1H), 8.70 (d, 2H, J = 6.1 Hz), 8.27 (s, 1H), (methylsulfonamido)-1H- 8.12 (s, 1H), 7.65~7.73 (m, 1H), 7.73 (d, 2H, J = 6.1 Hz), indole-2-carboxamide 7.57~7.60 (m, 2H), 7.35~7.42 (m, 3H), 7.26 (dt, 1H, J = 8.4, 1.9 Hz), 7.00 (dd, 1H, J = 8.8, 1.9 Hz), 2.95 (s, 3H) 357 N-(2′,4′-difluoro-5- LC/MS ESI (+): 519 (M + 1) (pyridin-3-yl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 10.41 (s, biphenyl]-3-yl)-6- 1H), 9.64 (brs, 1H), 8.94 (s, 1H), 8.61 (d, 1H, J = 5.0 Hz), (methylsulfonamido)-1H- 8.05~8.20 (m, 3H), 7.74~7.78 (m, 1H), 7.63~7.67 (m, 1H), indole-2-carboxamide 7.51~7.58 (m, 2H), 7.36~7.47 (m, 3H), 7.26 (dt, 1H, J = 8.4, 1.9 Hz), 6.99 (dd, 1H, J = 8.4, 1.9 Hz), 2.94 (s, 3H) 358 N-(2′,4′-difluoro-5-(6- LC/MS ESI (+): 587 (M + 1) (trifluoromethyl)pyridin- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.76 (s, 1H), 10.47 (s, 3-yl)-[1,1′-biphenyl]-3- 1H), 9.67 (brs, 1H), 9.15 (s, 1H), 8.42 (d, 1H, J = 8.0 Hz), yl)-6- 8.28 (s, 1H), 8.13 (s, 1H), 8.04 (d, 1H, J = 8.4 Hz), (methylsulfonamido)-1H- 7.72~7.80 (m, 1H), 7.65~7.77 (m, 2H), 7.39~7.46 (m, 3H), 7.25 (dt, indole-2-carboxamide 1H, J = 8.8, 2.3 Hz), 7.00 (dd, 1H, J = 8.4, 1.9 Hz), 2.96 (s, 3H) 359 N-(5-(6-cyanopyridin-3- LC/MS ESI (+): 544 (M + 1) yl)-2′,4′-difluoro-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.75 (s, 1H), 10.46 (s, biphenyl]-3-yl)-6- 1H), 9.66 (brs, 1H), 9.15 (s, 1H), 8.41 (dd, 1H, J = 8.0, (methylsulfonamido)-1H- 2.3 Hz), 8.27 (s, 1H), 8.15~8.18 (m, 2H), 7.64~7.82 (m, indole-2-carboxamide 3H), 7.39~7.47 (m, 3H), 7.27 (dt, 1H, J = 8.8, 2.3 Hz), 7.00 (dd, 1H, J = 8.8, 1.9 Hz), 2.95 (s, 3H) 360 N-(2′,4′-difluoro-5- LC/MS ESI (+): 520 (M + 1) (pyrimidin-5-yl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.76 (s, 1H), 10.45 (s, biphenyl]-3-yl)-6- 1H), 9.67 (brs, 1H), 9.25 (s, 1H), 9.19 (s, 2H), 8.23 (s, 1H), (methylsulfonamido)-1H- 8.13 (s, 1H), 7.73~7.81 (m, 1H), 7.65~7.68 (m, 2H), indole-2-carboxamide 7.41~7.46 (m, 3H), 7.27 (dt, 1H, J = 8.8, 1.9 Hz), 7.00 (dd, 1H, J = 8.4, 1.9 Hz), 2.96 (s, 3H) 361 N-(5-(2-aminopyrimidin- LC/MS ESI (+): 535 (M + 1) 5-yl)-2′,4′-difluoro-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.72 (s, 1H), 10.33 (s, biphenyl]-3-yl)-6- 1H), 9.64 (brs, 1H), 8.62 (s, 2H), 8.05 (s, 1H), 7.99 (s, 1H), (methylsulfonamido)-1H- 7.71~7.74 (m, 1H), 7.64 (d, 1H, J = 8.5 Hz), 7.48 (s, 1H), indole-2-carboxamide 7.34~7.45 (m, 3H), 7.25 (dt, 1H, J = 7.7, 1.8 Hz), 7.00 (dd, 1H, J = 8.8, 1.8 Hz), 6.87 (s, 2H), 2.94 (s, 3H) 362 6-(methylsulfonamido)-N- LC/MS ESI (+): 554 (M + 1) (2,2″,4,4″-tetrafluoro- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.70 (s, 1H), 10.38 (s, [1,1′:3′,1″-terphenyl]-5′- 1H), 9.68 (s, 1H), 8.07 (s, 2H), 7.62~7.73 (m, 3H), yl)-1H-indole-2- 7.37~7.46 (m, 5H), 7.25 (td, 2H, J = 8.4, 2.7 Hz), 6.98 (dd, carboxamide 1H, J = 8.8, 1.9 Hz), 2.93 (s, 3H) 363 N-(5-(cyanomethyl)-2′,4′- LC/MS ESI (+): 481 (M + 1) difluoro-[1,1′-biphenyl]-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.72 (s, 1H), 10.38 (s, yl)-6- 1H), 9.65 (brs, 1H), 7.97 (s, 1H), 7.94 (s, 1H), 7.64 (d, 1H, (methylsulfonamido)-1H- J = 8.4 Hz), 7.56~7.66 (m, 1H), 7.38~7.46 (m, 3H), indole-2-carboxamide 7.21~7.28 (m, 2H), 6.99 (dd, 1H, J = 8.4, 1.5 Hz), 4.16 (s, 2H), 2.94 (s, 3H)

Example 364 Synthesis of N-(2′,4′-difluoro-5-(6-hydroxypyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 5-(5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)pyridin-2-ol

2′,4′-Difluoro-5-(6-fluoropyridin-3-yl)[1,1′-biphenyl]-3-amine (32.0 mg, 0.11 mmol) was dissolved in 1,4-dioxane (2.0 mL), and a mixture of 6 N HCl/1,4-dioxane (444.0 μL) was slowly added at 0° C. The mixture was stirred at 100° C. for 2 hours, and then basified with sat. NaHCO₃ aqueous solution (pH 9), and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=1:1) to obtain 5-(5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)pyridin-2-ol (20.0 mg, 63%) as a yellow solid.

LC/MS ESI (+): 299 (M+1)

(b) Synthesis of N-(2′,4′-difluoro-5-(6-hydroxypyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(methylsulfonamido)-1H-indole-2-carboxylic acid (29.0 mg, 0.10 mmol), 5-(5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)pyridin-2-ol (30.0 mg, 0.10 mmol), HATU (42.0 mg, 0.11 mmol), and DIPEA (26.0 μL, 0.15 mmol) were dissolved in anhydrous DMF (2.0 mL), followed by stirring at 40° C. for 12 hours. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was firstly purified by flash column chromatography, and the residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=1:1) to obtain N-(2′,4′-difluoro-5-(6-hydroxypyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (7.6 mg, 14%) as a white solid.

LC/MS ESI (+): 535 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.82 (brs, 1H), 11.65 (s, 1H), 10.25 (s, 1H), 9.57 (s, 1H), 7.95-8.00 (m, 2H), 7.86 (dd, 1H, J=9.5, 3.0 Hz), 7.63-7.77 (m, 3H), 7.34-7.42 (m, 4H), 7.23 (dt, 1H, J=8.3, 2.8 Hz), 7.00 (dd, 1H, J=8.6, 1.9 Hz), 6.49 (d, 1H, J=9.3 Hz), 2.95 (s, 3H)

Example 365 Synthesis of N-(5-ethynyl-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 2′,4′-difluoro-5-((trimethylsilyl)ethynyl)-[1,1′-biphenyl]-3-amine

5-Bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (100.0 mg, 0.35 mmol), ethynyltrimethylsilane (149.0 μL, 1.06 mmol), Pd(t-Bu₃P)₂ (180.0 mg, 0.04 mmol), CuI (67.0 mg, 0.04 mmol), and Et₃N (147.0 μL, 1.06 mmol) were added to 1,4-dioxane (3.0 mL), followed by stirring at 40° C. for 17 minutes, and the reaction mixture was cooled to room temperature and then extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain 2′,4′-difluoro-5-((trimethylsilyl)ethynyl)-[1,1′-biphenyl]-3-amine (75.0 mg, 71%) as a white solid.

LC/MS ESI (+): 302 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 7.36 (m, 1H), 7.00 (m, 1H), 6.84-6.95 (m, 2H), 6.76-6.80 (m, 2H), 3.72 (brs, 2H), 1.57 (s, 9H)

(b) Synthesis of 5-ethynyl-2′,4′-difluoro-[1,1′-biphenyl]-3-amine

2′,4′-Difluoro-5-((trimethylsilyl)ethynyl)-[1,1′-biphenyl]-3-amine (71.0 mg, 0.24 mmol) was dissolved in anhydrous MeOH (2.0 mL), and K₂CO₃ (33.0 mg, 0.24 mmol) was added. The reaction mixture was stirred at 17° C. for 3 hours, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=20:1) to obtain 5-ethynyl-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (45.0 mg, 83%) as a yellow solid.

LC/MS ESI (+): 230 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 7.36 (m, 1H), 7.00 (m, 1H), 6.86-6.96 (m, 2H), 6.80-6.83 (m, 2H), 3.72 (brs, 2H), 3.04 (s, 1H)

(c) Synthesis of N-(5-ethynyl-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(Methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (57.0 mg, 0.20 mmol), 5-ethynyl-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (45.0 mg, 0.20 mmol), HATU (82.0 mg, 0.22 mmol), and DIPEA (51.0 μL, 0.29 mmol) were dissolved in anhydrous DMF (2.0 mL), followed by stirring at 16° C. for 16 hours. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain N-(5-ethynyl-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (28.9 mg, 32%) as a white solid.

LC/MS ESI (+): 466 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 10.35 (s, 1H), 9.65 (s, 1H), 8.05 (m, 1H), 8.00 (m, 1H), 7.60-7.68 (m, 2H), 7.39-7.46 (m, 3H), 7.34 (m, 1H), 7.24 (dt, 1H, J=8.4, 2.5 Hz), 6.99 (dd, 1H, J=8.6, 1.9 Hz), 4.30 (s, 1H), 2.95 (s, 3H)

Example 366 Synthesis of N-(5-(2,2-difluoroethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 2′,4′-difluoro-5-nitro-[1,1′-biphenyl]-3-ol

2,4-Difluoro-3′-methoxy-5′-nitro-1,1′-biphenyl (753.0 mg, 2.84 mmol) was dissolved in anhydrous CH₂Cl₂ (28.4 mL), and 1.0 M solution of BBr₃ in CH₂Cl₂ (11.4 mL) was slowly added at 0° C. The mixture was stirred at 0° C. for 10 hours, MeOH was slowly added. The reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 2′,4′-difluoro-5-nitro-[1,1′-biphenyl]-3-ol (187.0 mg, 82%) as a yellow solid.

¹H-NMR (300 MHz, CDCl₃): δ 7.96 (s, 1H), 7.69-7.71 (m, 1H), 7.32-7.49 (m, 1H), 7.32-7.33 (m, 1H), 6.93-7.04 (m, 2H), 5.48 (s, 1H)

(b) Synthesis of 3′-(2,2-difluoroethoxy)-2,4-difluoro-5′-nitro-1,1′-biphenyl

2′,4′-Difluoro-5-nitro-[1,1′-biphenyl]-3-ol (100.0 mg, 0.40 mmol) was dissolved in anhydrous DMF (2.0 mL), and K₂CO₃ (110.0 mg, 0.80 mmol) and 2-iodo-1,1-difluoroethane (42.0 μL, 0.48 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=3:1) to obtain 3′-(2,2-difluoroethoxy)-2,4-difluoro-5′-nitro-1,1′-biphenyl (107.0 mg, 91%) as a white solid.

¹H-NMR (300 MHz, CDCl₃): δ 8.05 (s, 1H), 7.76-7.78 (m, 1H), 7.41-7.49 (m, 2H), 6.95-7.04 (m, 2H), 6.14 (tt, 1H, J=54.6, 3.8 Hz), 4.32 (td, 2H, J=12.6, 3.8 Hz)

(c) Synthesis of 5-(2,2-difluoroethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine

3′-(2,2-Difluoro ethoxy)-2,4-difluoro-5′-nitro-1,1′-biphenyl (107.0 mg, 0.34 mmol) was dissolved in a mixture of MeOH/H₂O (3.4 mL, 8/1 v/v), and Zn (333.0 mg, 5.09 mmol) and NH₄Cl (91.0 mg, 1.70 mmol) were added. The reaction mixture was ultrasonificated for 2 hours, filtered through Celite and concentrated under reduced pressure. The residue was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=1:1) to obtain 5-(2,2-difluoroethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (96.0 mg, 99%) as a colorless oil.

LC/MS ESI (+): 286 (M+1)

(d) Synthesis of N-(5-(2,2-difluoroethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(Methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (44.8 mg, 0.15 mmol), 5-(2,2-difluoroethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-amine (48.5 mg, 0.17 mmol), and HATU (64.6 mg, 0.17 mmol) were dissolved in anhydrous DMF (3.0 mL). DIPEA (40.0 μL, 0.23 mmol) was slowly added, followed by stirring at room temperature for 24 hours. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂MeOH=30:1) to obtain N-(5-(2,2-difluoroethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (8.7 mg, 11%) as a white solid.

LC/MS ESI (+): 522 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 10.27 (s, 1H), 9.64 (s, 1H), 7.60-7.68 (m, 4H), 7.36-7.44 (m, 3H), 7.23 (td, 1H, J=8.4, 1.9 Hz), 6.99 (dd, 1H, J=8.4, 1.9 Hz), 6.91 (s, 1H), 6.44 (tt, 1H, J=54.6, 3.4 Hz), 4.39 (td, 2H, J=14.9, 3.4 Hz), 2.94 (s, 3H)

Through the synthetic method according to Example 366, compounds from Example 367 to Example 370 were synthesized, and the data of each example are as follows.

TABLE 23 Ex. Compound Analysis data 367 N-(2′,4′-difluoro-5- LC/MS ESI (+): 514 (M + 1) isobutoxy-[1,1′-biphenyl]- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.70 (s, 1H), 10.21 (s, 3-yl)-6- 1H), 9.64 (s, 1H), 7.56~7.65 (m, 4H), 7.34~7.42 (m, 3H), (methylsulfonamido)-1H- 7.21 (td, 1H, J = 8.4, 2.3 Hz), 6.99 (dd, 1H, J = 8.8, 1.5 Hz), indole-2-carboxamide 6.80 (s, 1H), 3.81 (d, 2H, J = 6.5 Hz), 2.94 (s, 3H), 1.98~2.11 (m, 1H), 1.01 (d, 6H, J = 6.9 Hz) 368 N-(5-(cyanomethoxy)-2′,4′- LC/MS ESI (+): 497 (M + 1) difluoro-[1,1′-biphenyl]-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 10.34 (s, yl)-6-(methylsulfonamido)- 1H), 9.64 (s, 1H), 7.59~7.71 (m, 4H), 7.39~7.46 (m, 3H), 1H-indole-2-carboxamide 7.22~7.29 (m, 1H), 6.97~7.00 (m, 2H), 5.24 (s, 2H), 2.94 (s, 3H) 369 N-(5-(difluoromethoxy)- LC/MS ESI (+): 508 (M + 1) 2′,4′-difluoro-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.75 (s, 1H), 10.42 (s, biphenyl]-3-yl)-6- 1H), 9.65 (s, 1H), 7.84~7.85 (m, 2H), 7.60~7.69 (m, 2H), (methylsulfonamido)-1H- 7.40~7.47 (m, 3H), 7.32 (t, 1H, J = 74.0 Hz), 7.26 (dt, 1H, indole-2-carboxamide J = 8.8, 2.3 Hz), 7.07 (brs, 1H), 6.99 (dd, 1H, J = 8.6, 1.9 Hz), 2.94 (s, 3H) 370 N-(5-(difluoromethoxy)- LC/MS ESI (+): 525 (M + 1) 2′,4′-difluoro-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.73 (s, 1H), 9.80 (s, biphenyl]-3-yl)-5- 1H), 8.33 (s, 1H), 8.03 (d, 1H, J = 8.8 Hz), 7.81~7.84 (m, (methylsulfonamido)benzo[b]thiophene- 2H), 7.77 (s, 1H), 7.64 (m, 1H), 7.35~7.48 (m, 2H), 2-carboxamide 7.33 (t, 1H, J = 73.8 Hz), 7.26 (t, 1H, J = 8.1 Hz), 7.10 (s, 1H), 3.02 (s, 3H)

Example 371 Synthesis of N-(2′,4′-difluoro-5-(piperidin-1-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 1-(3-iodo-5-nitrophenyl)piperidine

1-Fluoro-3-iodo-5-nitrobenzene (500.0 mg, 1.87 mmol) was dissolved in anhydrous DMF (10.0 mL), and K₂CO₃ (518.0 mg, 3.75 mmol) and piperidine (185.0 μL, 1.87 mmol) were added. The mixture was stirred at 130° C. for 16 hours, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=10:1) to obtain 1-(3-iodo-5-nitrophenyl)piperidine (330.0 mg, 53%) as a white solid.

LC/MS ESI (+): 333 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 7.73 (s, 1H), 7.59-7.63 (m, 2H), 3.28-3.32 (m, 4H), 1.53-1.64 (m, 6H)

(b) Synthesis of 1-(2′,4′-difluoro-5-nitro-[1,1′-biphenyl]-3-yl)piperidine

1-(3-Iodo-5-nitrophenyl)piperidine (250.0 mg, 0.75 mmol), (2,4-difluorophenyl)boronic acid (125.0 mg, 0.79 mmol), Pd(PPh₃)4 (87.0 mg, 0.09 mmol) and Na₂CO₃ (239.0 mg, 2.26 mmol) were added to a mixture of DME/H₂O (7.5 mL, 4/1 v/v), followed by stirring at 85° C. for 4 hours. The reaction mixture was cooled to room temperature and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 1-(2′,4′-difluoro-5-nitro-[1,1′-biphenyl]-3-yl)piperidine (260.0 mg, 100%) as a white solid.

LC/MS ESI (+): 319 (M+1)

(c) Synthesis of 2′,4′-difluoro-5-(piperidin-1-yl)-[1,1′-biphenyl]-3-amine

1-(2′,4′-Difluoro-5-nitro-[1,1′-biphenyl]-3-yl)piperidine (260.0 mg, 0.82 mmol) was dissolved in a mixture of THF/MeOH/H₂O (10.0 mL, 1/2/0.5 v/v), and Zn (534.0 mg, 8.17 mmol) and NH₄Cl (131.0 mg, 2.45 mmol) were added at room temperature. The reaction mixture was ultrasonificated for 1 hour, cooled to room temperature, filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH₂Cl₂:MeOH=97:3) to obtain 2′,4′-difluoro-5-(piperidin-1-yl)-[1,1′-biphenyl]-3-amine (98.0 mg, 42%) as an off-white solid.

LC/MS ESI (+): 289 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 7.46 (td, 1H, J=9.0, 6.9 Hz), 7.23-7.30 (m, 1H), 7.11 (m, 1H), 6.18-6.19 (m, 2H), 6.14 (m, 1H), 4.99 (s, 2H), 3.05-3.19 (m, 4H), 1.51-1.59 (m, 6H)

(d) Synthesis of N-(2′,4′-difluoro-5-(piperidin-1-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(Methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (50.0 mg, 0.17 mmol), 2′,4′-difluoro-5-(piperidin-1-yl)-[1,1′-biphenyl]-3-amine (50.0 mg, 0.17 mmol), HATU (72.0 mg, 0.19 mmol), and DIPEA (45.0 μL, 0.26 mmol) were dissolved in anhydrous DMF (3.0 mL), followed by stirring at 40° C. for 14 hours. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH₂Cl₂:MeOH=30:1) to obtain N-(2′,4′-difluoro-5-(piperidin-1-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (23.0 mg, 26%) as a white solid.

LC/MS ESI (+): 525 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.65 (s, 1H), 10.06 (s, 1H), 9.61 (brs, 1H), 7.54-7.64 (m, 2H), 7.44-7.46 (m, 2H), 7.31-7.39 (m, 3H), 7.19 (dt, 1H, J=8.4, 2.5 Hz), 6.98 (d, 1H, J=8.4 Hz), 6.76 (brs, 1H), 3.20-3.23 (m, 4H), 2.94 (s, 3H), 1.57-1.65 (m, 6H)

Through the synthetic method according to Example 371, compounds from Example 372 to Example 376 were synthesized, and the data of each example are as follows.

TABLE 24 Ex. Compound Analysis data 372 N-(5-(dimethylamino)-2′,4′- LC/MS ESI (+): 485 (M + 1) difluoro-[1,1′-biphenyl]-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.67 (s, 1H), 10.07 (s, yl)-6-(methylsulfonamido)- 1H), 9.63 (brs, 1H), 7.55~7.65 (m, 2H), 7.30~7.40 (m, 1H-indole-2-carboxamide 5H), 7.20 (dt, 1H, J = 8.8, 2.5 Hz), 6.99 (dd, 1H, J = 8.6, 1.5 Hz), 6.56 (brs, 1H), 2.97 (s, 6H), 2.95 (s, 3H) 373 N-(2′,4′-difluoro-5- LC/MS ESI (+): 471 (M + 1) (methylamino)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.6 (s, 1H), 10.0 (s, biphenyl]-3-yl)-6- 1H), 9.55 (brs, 1H), 7.62 (d, 1H, J = 8.6 Hz), 7.54 (m, 1H), (methylsulfonamido)-1H- 7.35 (m, 3H), 7.18 (m, 3H), 6.98 (dd, 1H, J = 8.6, 1.5 Hz), indole-2-carboxamide 6.40 (m, 1H), 5.90 (m, 1H), 2.93 (s, 3H), 2.72 (d, 3H, J = 5.0 Hz) 374 N-(2′,4′-difluoro-5- LC/MS ESI (+): 527 (M + 1) morpholine-[1,1′-biphenyl]- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.66 (s, 1H), 10.11 (s, 3-yl)-6- 1H), 9.61 (brs, 1H), 7.55~7.64 (m, 2H), 7.46~7.50 (m, (methylsulfonamido)-1H- 2H), 7.32~7.39 (m, 3H), 7.20 (dt, 1H, J = 8.8, 2.5 Hz), indole-2-carboxamide 6.98 (dd, 1H, J = 8.8, 1.5 Hz), 6.80 (brs, 1H), 3.77 (t, 4H, J = 4.6 Hz), 3.17 (t, 4H, J = 4.6 Hz), 2.94 (s, 3H) 375 N-(5-(dimethylamino)-2′,4′- LC/MS ESI (+): 502 (M + 1) difluoro-[1,1′-biphenyl]-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.37 (s, 1H), 9.87 (s, yl)-5- 1H), 8.33 (s, 1H), 8.02 (d, 1H, J = 8.4 Hz), 7.80 (d, 1H, (methylsulfonamido)benzo[b]thiophene- J = 1.9 Hz), 7.54~7.62 (m, 1H), 7.30~7.39 (m, 3H), 2-carboxamide 7.16~7.25 (m, 2H), 6.58 (s, 1H), 3.02 (s, 3H), 2.96 (s, 6H) 376 N-(5-(dimethylamino)-2′,4′- LC/MS ESI (+): 486 (M + 1) difluoro-[1,1′-biphenyl]-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.41 (s, 1H), 9.75 (s, yl)-5- 1H), 7.74 (s, 1H), 7.70 (d, 1H, J = 8.8 Hz), 7.65 (s, 1H), (methylsulfonamido)benzofuran- 7.53~7.61 (m, 1H), 7.31~7.38 (m, 3H), 7.28 (s, 1H), 2-carboxamide 7.19 (td, 1H, J = 8.4, 2.7 Hz), 6.58 (s, 1H), 2.98 (s, 3H), 2.95 (s, 6H)

Example 377 Synthesis of N-(5′-carbamoyl-4′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 4-methoxy-3′46-(methylsulfonamido)-1H-indole-2-carboxamido)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylic acid

Methyl 4-methoxy-3′(6-(methylsulfonamido)-1H-indole-2-carboxamido)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylate (30.0 mg, 0.05 mmol) was dissolved in MeOH (1.0 mL), and 1 N NaOH aqueous solution (300.0 μL) was added. The reaction mixture was stirred at 10° C. for 17 hours, acidified to pH 3 with 1 N HCl aqueous solution and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure to obtain 4-methoxy-3′-(6-(methylsulfonamido)-1H-indole-2-carboxamido)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylic acid (29.0 mg, 99%) as a white solid.

LC/MS ESI (+): 548 (M+1)

(b) Synthesis of N-(5′-carbamoyl-4′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

4-Methoxy-3′-(6-(methylsulfonamido)-1H-indole-2-carboxamido)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylic acid (29.0 mg, 0.05 mmol), NH₄Cl (14.0 mg, 0.27 mmol), EDC (15.0 mg, 0.08 mmol), and HOBt (11.0 mg, 0.08 mmol) were dissolved in anhydrous DMF (3.0 mL), and DIPEA (28.0 μL, 0.20 mmol) was added. After stirring at 7° C. for 16 hours, the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH₂Cl₂:MeOH=20:1) to obtain N-(5′-carbamoyl-4′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (3.0 mg, 10%) as a white solid.

LC/MS ESI (+): 547 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 10.26 (s, 1H), 9.63 (s, 1H), 7.77-7.88 (m, 4H), 7.68 (s, 1H), 7.63 (d, 1H, J=8.6 Hz), 7.37-7.48 (m, 4H), 6.96-7.04 (m, 2H), 4.02 (s, 3H), 2.94 (s, 3H)

Example 378 Synthesis of N-(5′-carbamoyl-4′-hydroxy-T-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

N-(5′-carbamoyl-4′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (25.0 mg, 0.05 mmol) was dissolved in anhydrous CH₂Cl₂ (2.0 mL), and 1.0 M solution of BBr₃ in CH₂Cl₂ (229.0 μL) was slowly added at 0° C. After stirring at 7° C. for 17 hours, MeOH was slowly added, followed by extracting with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH₂Cl₂:MeOH=20:1) to obtain N-(5′-carbamoyl-4′-hydroxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (2.0 mg, 8%) as a white solid.

LC/MS ESI (+): 533 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 13.26 (s, 1H), 11.73 (s, 1H), 10.26 (s, 1H), 9.64 (s, 1H), 8.61 (brs, 1H), 8.17 (brs, 1H), 7.97 (s, 1H), 7.86-7.89 (m, 1H), 7.80 (m, 1H), 7.63 (d, 1H, J=8.6 Hz), 7.39-7.45 (m, 3H), 7.31 (s, 1H), 7.03-7.06 (m, 1H), 6.98 (dd, 1H, J=8.8, 1.7 Hz), 2.94 (s, 3H)

Through the synthetic method according to Example 377, compounds from Example 379 to Example 381 were synthesized, and the data of each example are as follows.

TABLE 25 Ex. Compound Analysis data 379 N-(5′-carbamoyl-2′- LC/MS ESI (+): 517 (M + 1) (trifluoromethyl)-[1,1′- ¹H-NMR (500 MHz, DMSO-d₆): δ 11.71 (s, 1H), 10.26 (s, biphenyl]-3-yl)-6- 1H), 9.62 (s, 1H), 8.24 (s, 1H), 8.09 (d, 1H, J = 8.1 Hz), (methylsulfonamido)-1H- 7.97 (d, 1H, J = 8.6 Hz) 7.94 (s, 1H), 7.90 (d, 1H, J = 7.0 Hz), indole-2-carboxamide 7.86 (s, 1H), 7.62~7.66 (m, 2H), 7.47 (t, 1H, J = 8.0 Hz), 7.40 (m, 2H), 7.09 (d, 1H, J = 7.3 Hz), 6.99 (d, 1H, J = 9.0 Hz), 2.94 (s, 3H) 380 N-(5′-carbamoyl-2′- LC/MS ESI (+): 483 (M + 1) chloro-[1,1′-biphenyl]-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 10.30 (s, yl)-6- 1H), 9.94 (s, 1H), 8.14 (s, 1H), 7.89~7.97 (m, 4H), 7.67 (d, (methylsulfonamido)-1H- 1H, J = 8.1 Hz), 7.62 (d, 1H, J = 8.7 Hz), 7.46~7.52 (m, 2H), indole-2-carboxamide 7.40 (d, 2H, J = 5.4 Hz), 7.20 (d, 1H, J = 7.2 Hz), 6.97 (dd, 1H, J = 8.7, 1.8 Hz), 2.94 (s, 3H) 381 N-(4-(5-carbamoyl-2- LC/MS ESI (+): 484 (M + 1) chlorophenyl)pyridin-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.75 (s, 1H), 10.99 (s, yl)-6- 1H), 9.67 (s, 1H), 8.50 (d, 1H, J = 5.4 Hz), 8.37 (s, 1H), (methylsulfonamido)-1H- 8.17 (s, 1H), 7.95~8.00 (m, 2H), 7.73 (d, 1H, J = 8.4 Hz), indole-2-carboxamide 7.56~7.62 (m, 3H), 7.39 (s, 1H), 7.29 (dd, 1H, J = 3.6, 1.2 Hz), 6.96 (dd, 1H, J = 8.4, 1.5 Hz), 2.94 (s, 3H)

Example 382 Synthesis of N-(2′,4′-difluoro-5-(6-methoxypyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (30.0 mg, 0.06 mmol), (6-methoxypyridin-3-yl)boronic acid (11.0 mg, 0.07 mmol), Pd(PPh₃)₄ (20.0 mg, 0.02 mmol) and Na₂CO₃ (18.0 mg, 0.17 mmol) were added to a mixture of DME/H₂O (0.6 mL, 5/1 v/v), followed by stirring at 80° C. for 14 hours. The reaction mixture was cooled to room temperature and then extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain N-(2′,4′-difluoro-5-(6-methoxypyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (4.0 mg, 13%) as a white solid.

LC/MS ESI (+): 549 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.71 (s, 1H), 10.37 (s, 1H), 9.64 (brs, 1H), 8.51 (d, 1H, J=2.4 Hz), 8.09 (s, 1H), 8.05 (dd, 1H, J=8.3, 2.4 Hz), 8.01 (s, 1H), 7.69-7.73 (m, 1H), 7.62 (d, 1H, J=8.8 Hz), 7.48 (s 1H), 7.37-7.42 (m, 3H), 7.24 (dt, 1H, J=8.3, 2.4 Hz), 6.97 (dd, 1H, J=8.8, 2.0 Hz), 6.95 (d, 1H, J=8.8 Hz), 3.90 (s, 3H), 2.93 (s, 3H)

Through the synthetic method according to Example 382, compound of Example 383 was synthesized, and the data of the example are as follows.

TABLE 26 Ex. Compound Analysis data 383 N-(2′,4′-difluoro-5-(6- LC/MS ESI (+): 549 (M + 1) methoxypyridin-2-yl)-[1,1′- ¹H-NMR (300 MHz, DMSO-d₆): biphenyl]-3-yl)-6- δ 11.75 (s, 1H), 10.40 (s, 1H), 9.63 (methylsulfonamido)-1H- (brs, 1H), 8.62 (s, 1H), 8.08 (s, 1H), indole-2-carboxamide 7.92 (s, 1H), 7.84 (t, 1H, J = 7.9 Hz), 7.57~7.77 (m, 4H), 7.40~7.47 (m, 2H), 7.27 (t, 1H, J = 8.8 Hz), 6.98 (dd, 1H, J = 8.3, 1.9 Hz), 6.84 (d, 1H, J = 8.3 Hz), 3.99 (s, 3H), 2.94 (s, 3H)

Example 384 Synthesis of N-(2′,4′-difluoro-5-(6-hydroxypyridin-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

N-(2′,4′-difluoro-5-(6-methoxypyridin-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (13.0 mg, 0.02 mmol) was dissolved in anhydrous CH₂Cl₂ (28.4 mL), and 1.0 M solution of BBr₃ in CH₂Cl₂ (118.0 μL) was slowly added at 0° C. The reaction mixture was stirred at 25° C. for 17 hours, and MeOH was slowly added. The reaction mixture was extracted with EtOAc and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=3:1) to obtain N-(2′,4′-difluoro-5-(6-hydroxypyridin-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (3.0 mg, 24%) as a white solid.

LC/MS ESI (+): 535 (M+1)

¹H-NMR (300 MHz, CD₃OD): δ 8.14 (t, 1H, J=1.9 Hz), 8.00 (m, 1H), 7.63-7.72 (m, 3H), 7.58 (m, 1H), 7.47 (m, 1H), 7.36 (d, 1H, J=0.9 Hz), 7.09-7.16 (m, 2H), 7.01 (dd, 1H, J=8.6, 1.9 Hz), 6.73 (m, 1H), 6.57 (m, 1H), 2.96 (s, 3H)

Example 385 Synthesis of N-(4′-amino-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(Methyl sulfonamido)-N-(4′-nitro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide (48.0 mg, 0.09 mmol) was dissolved in a mixture of MeOH/H₂O (10.0 mL, 9/1 v/v), and Zn (90.0 mg, 1.38 mmol) and NH₄Cl (25.0 mg, 0.46 mmol) were added. The reaction mixture was ultrasonificated for 2 hours, filtered through Celite and concentrated under reduced pressure. The residue was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=20:1) to obtain N-(4′-amino-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (30.0 mg, 67%) as a colorless oil.

LC/MS ESI (+): 489 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.72 (s, 1H), 10.19 (s, 1H), 9.63 (brs, 1H), 7.79 (d, 1H, J=9.5 Hz), 7.73 (s, 1H), 7.62 (d, 1H, J=8.4 Hz), 7.33-7.41 (m, 3H), 7.04 (d, 1H, J=8.4 Hz), 6.94-7.00 (m, 3H), 6.82 (dd, 1H, J=7.3, 1.5 Hz), 5.66 (brs, 2H), 2.93 (s, 3H)

Example 386 Synthesis of N-(4′-(methylamino)-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

N-(4′-amino-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (30.0 mg, 0.06 mmol) was dissolved in triethoxymethane (2.0 mL), and a catalytic amount of TFA was added. After stirring at 80° C. for 4 hours, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOH (2.0 mL), and NaBH₄ (23.0 mg, 0.61 mmol) was added. After stirring at 70° C. for 2 hours, the reaction mixture was concentrated under reduced pressure, and the residue was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH₂Cl₂:MeOH=20:1) to obtain N-(4′-(methylamino)-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(meth yl sulfonamido)-1H-indole-2-carboxamide (6.0 mg, 20%) as a white solid.

LC/MS ESI (+): 503 (M+1)

¹H-NMR (300 MHz, CDCl₃): δ 11.71 (s, 1H), 10.19 (s, 1H), 9.63 (brs, 1H), 7.80 (d, 1H, J=8.8 Hz), 7.74 (s, 1H), 7.62 (d, 1H, J=8.4 Hz), 7.33-7.41 (m, 3H), 7.13 (d, 1H, J=8.4 Hz), 6.97 (d, 1H, J=1.5 Hz), 6.96 (d, 1H, J=1.9 Hz), 6.90 (d, 1H, J=2.3 Hz), 6.81 (dd, 1H, J=8.4, 1.9 Hz), 6.25 (q, 1H, J=5.0 Hz), 2.93 (s, 3H), 2.75 (d, 3H, J=5.0 Hz)

Example 387 Synthesis of N-(3-(difluoro(phenyl)methyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 1-(difluoro(phenyl)methyl)-3-nitrobenzene

(3-Nitrophenyl)(phenyl)methanone (0.3 g, 1.32 mmol) was dissolved in CH₂Cl₂ (2.0 mL) in a sealed tube, and 50% solution of Deoxo-Fluor in THF (7.9 mL, 3.96 mmol) was added. THF was distilled under reduced pressure, followed by stirring at 90° C. for 8 hours. The reaction mixture was cooled to room temperature and extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 1-(difluoro(phenyl)methyl)-3-nitrobenzene (280.0 mg, 85%) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃): δ 8.39 (s, 1H), 8.31 (d, 1H, J=8.0 Hz), 7.85 (d, 1H, J=7.6 Hz), 7.63 (t, 1H, J=8.0 Hz), 7.44-7.53 (m, 5H)

(b) Synthesis of 3-(difluoro(phenyl)methyl)aniline

1-(Difluoro(phenyl)methyl)-3-nitrobenzene (280.0 mg, 1.12 mmol) was dissolved in MeOH (5.0 mL). Under an atmosphere of hydrogen gas, Ra—Ni (100.0 mg, 1.70 mmol) was added, followed by stirring at room temperature for 1 hour. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=4:1) to obtain 3-(difluoro(phenyl)methyl)aniline (200.0 mg, 81%) as a white solid.

LC/MS ESI (+): 220 (M+1)

(c) Synthesis of N-(3-(difluoro(phenyl)methyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(Methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (35.0 mg, 0.14 mmol), 3-(difluoro(phenyl)methyl)aniline (30.0 mg, 0.14 mmol), and HATU (57.0 mg, 0.15 mmol) were dissolved in anhydrous DMF (1.4 mL), and DIPEA (37.0 μL, 0.21 mmol) was added. After stirring at room temperature for 15 hours, the reaction mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=95:5) to obtain N-(3-(difluoro(phenyl)methyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (23.0 mg, 36%) as a white solid.

LC/MS ESI (+): 456 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 10.34 (s, 1H), 9.64 (s, 1H), 7.96-8.00 (m, 2H), 7.63 (d, 1H, J=8.8 Hz), 7.47-7.56 (m, 6H), 7.39 (s, 2H), 7.26 (d, 1H, J=7.6 Hz), 6.98 (dd, 1H, J=8.4, 1.9 Hz), 2.94 (s, 3H)

Through the synthetic method according to Example 387, compounds from Example 388 to Example 390 were synthesized, and the data of each example are as follows.

TABLE 27 Ex. Compound Analysis data 388 N-(3-(difluoro(pyridin- LC/MS ESI (+): 457 (M + 1) 4-yl)methyl)phenyl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.75 (s, 1H), 10.36 (s, (methylsulfonamido)- 1H), 9.64 (s, 1H), 8.77 (d, 2H, J = 6.1 Hz), 7.97~8.01 (m, 2H), 1H-indole-2- 7.63 (d, 1H, J = 8.4 Hz), 7.58 (d, 2H, J = 6.1 Hz), 7.52 (t, 1H, carboxamide J = 8.0 Hz), 7.39 (s, 2H), 7.29 (d, 1H, J = 8.4 Hz), 6.98 (dd, 1H, J = 8.5, 1.7 Hz), 2.94 (s, 3H) 389 N-(3-(difluoro(pyridin- LC/MS ESI (+): 457 (M + 1) 2-yl)methyl)phenyl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.73 (s, 1H), 10.34 (s, (methylsulfonamido)- 1H), 9.64 (s, 1H), 8.66 (d, 1H, J = 5.0 Hz), 7.96~8.02 (m, 3H), 1H-indole-2- 7.84 (d, 1H, J = 7.6 Hz), 7.63 (d, 1H, J = 8.8 Hz), 7.55 (dd, 1H, carboxamide J = 7.6, 4.6 Hz), 7.48 (t, 1H, J = 7.6 Hz), 7.39 (dd, 2H, J = 5.3, 1.9 Hz), 7.28 (d, 1H, J = 8.8 Hz), 6.98 (dd, 1H, J = 8.8, 1.9 Hz), 2.94 (s, 3H) 390 N-(3-((3- LC/MS ESI (+): 481 (M + 1) cyanophenyl)difluoromethyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.76 (s, 1H), 10.36 (s, 6- 1H), 9.65 (s, 1H), 8.11 (s, 1H), 7.98~8.07 (m, 3H), (methylsulfonamido)- 7.90 (d, 1H, J = 8.4 Hz), 7.76 (t, 1H, J = 8.0 Hz), 7.64 (d, 1H, 1H-indole-2- J = 8.0 Hz), 7.53 (t, 1H, J = 8.8 Hz), 7.40 (s, 2H), 7.31 (d, 1H, carboxamide J = 8.0 Hz), 6.99 (dd, 1H, J = 8.4, 1.9 Hz), 2.95 (s, 3H)

Example 391 Synthesis of N-(3-((3-cyanophenyl)difluoromethyl)-5-(2,2-difluoroethoxy)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 4-methoxybenzyl 3-((4-methoxybenzyl)oxy)-5-nitrobenzoate

3-Hydroxy-5-nitrobenzoic acid (5.0 g, 27.17 mmol) was dissolved in anhydrous DMF (60.0 mL), and K₂CO₃ (15.0 g, 108.68 mmol) and 4-methoxybenzyl chloride (11.1 mL, 81.51 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, and heated at 65° C. for 3 hours, water was added to quench the reaction. The reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was recrystallized with a mixture of EtOAc/n-Hex, and the precipitate was filtered to obtain 4-methoxybenzyl 3-((4-methoxybenzyl)oxy)-5-nitrobenzoate (10.6 g, 92%) as a yellow solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 8.18 (m, 1H), 8.03 (m, 1H), 7.87 (m, 1H), 7.39-7.44 (m, 4H), 6.93-6.97 (m, 4H), 5.31 (s, 2H), 5.22 (s, 2H), 3.76 (s, 3H), 3.75 (s, 3H)

(b) Synthesis of 3-((4-methoxybenzyl)oxy)-5-nitrobenzoic acid

4-Methoxybenzyl 3-((4-methoxybenzyl)oxy)-5-nitrobenzoate (1.5 g, 3.54 mmol) was dissolved in a mixture of MeOH/THF/H₂O (32.0 mL, 2/1/0.5 v/v), and NaOH (283.0 mg, 7.08 mmol) was added, followed by stirring at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in water. 1 N HCl was added for the acidification to pH 1-2, and the precipitate was filtered and dried under reduced pressure to obtain 3-((4-methoxybenzyl)oxy)-5-nitrobenzoic acid (1.1 g, 98%) as an off-white solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 13.78 (brs, 1H), 8.21 (m, 1H), 8.02 (m, 1H), 7.88 (m, 1H), 7.42 (d, 2H, J=8.4 Hz), 6.97 (d, 2H, J=8.8 Hz), 5.23 (s, 2H), 3.76 (s, 3H)

(c) Synthesis of 3-((4-methoxybenzyl)oxy)-5-nitrobenzoyl chloride

3-((4-Methoxybenzyl)oxy)-5-nitrobenzoic acid (472.0 mg, 1.56 mmol) was dissolved in anhydrous CH₂Cl₂ (20.0 mL), and (COCl)₂ (149.0 μL, 1.71 mmol) and a catalytic amount of anhydrous DMF were added. After stirring at 0° C. for 2 hours, the reaction mixture was dried under reduced pressure to obtain 3-(4-methoxybenzyl)oxy)-5-nitrobenzoyl chloride (501.9 mg) as a yellow solid.

(d) Synthesis of 3-(3-((4-methoxybenzyl)oxy)-5-nitrobenzo yl)benzonitrile

To a solution of crude 3-((4-methoxybenzyl)oxy)-5-nitrobenzoyl chloride (501.9 mg), and Pd₂(dba)₃.CHCl₃ (80.5 mg, 0.08 mmol) in anhydrous THF (15.0 mL), 0.5 M solution of 3-cyanophenylzinc iodide in THF (3.42 mL, 1.71 mmol) was added at 0° C., followed by stirring for 41 hours. Water was added to quench the reaction, and the reaction mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=3:1) to obtain 3-(3-((4-methoxybenzyl)oxy)-5-nitrobenzoyl)benzonitrile (181.8 mg, 2 step yield: 30%) as an off-white solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 8.17-8.21 (m, 2H), 8.06-8.10 (m, 2H), 8.02 (m, 1H), 7.79 (t, 1H, J=8.0 Hz), 7.74 (m, 1H), 7.42 (d, 2H, J=8.4 Hz), 6.97 (d, 2H, J=8.4 Hz) 5.25 (s, 2H), 3.76 (s, 3H)

(e) Synthesis of 3-(difluoro(3-((4-methoxybenzyl)oxy)-5-nitrophenyl)methyl)benzonitrile

In 3-(3-((4-methoxybenzyl)oxy)-5-nitrobenzoyl)benzonitrile (180.0 mg, 0.46 mmol) in a sealed tube, 50% solution of Deoxo-Fluor in THF (985.0 μL, 2.32 mmol) was added, and THF was distilled under reduced pressure, followed by stirring at 90° C. for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 3-(difluoro(3-((4-methoxybenzyl)oxy)-5-nitrophenyl)methyl)benzonitrile (100.6 mg, 53%) as a yellow oil.

¹H-NMR (300 MHz, DMSO-d₆): δ 8.25 (s, 1H), 7.98-8.03 (m, 3H), 7.92 (m, 1H), 7.69-7.75 (m, 2H), 7.40 (d, 2H, J=8.4 Hz), 6.94 (d, 2H, J=8.8 Hz), 5.21 (s, 2H), 3.75 (s, 3H)

(f) Synthesis of 3-(difluoro(3-hydroxy-5-nitrophenyl)methyl)benzonitrile

3-(Difluoro(3-((4-methoxybenzyl)oxy)-5-nitrophenyl)methyl)benzonitrile (455.0 mg, 1.11 mmol) was dissolved in CH₂Cl₂ (5.0 mL), and TFA (2.5 mL) was added at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. The residue was extracted with CH₂Cl₂, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain 3-(difluoro(3-hydroxy-5-nitrophenyl)methyl)benzonitrile (300.0 mg, 100%) as a colorless oil.

¹H-NMR (300 MHz, DMSO-d₆): δ 11.07 (brs, 1H), 8.20 (s, 1H), 8.02 (d, 1H, J=8.0 Hz), 7.97 (d, 1H, J=8.0 Hz), 7.79 (s, 1H), 7.73 (t, 1H, J=8.0 Hz), 7.66 (t, 1H, J=2.3 Hz), 7.36 (t, 1H, J=1.9 Hz)

(g) Synthesis of 3-((3-(2,2-difluoroethoxy)-5-nitrophenyl)difluoromethyl)benzonitrile

3-(Difluoro(3-hydroxy-5-nitrophenyl)methyl)benzonitrile (120.0 mg, 0.41 mmol) was dissolved in toluene (5.0 mL), and 2,2-difluoroethanol (52.0 μL, 0.83 mmol) and (cyanomethylene)tributylphosphorane (216.0 μL, 0.83 mmol) were added, followed by stirring at 120° C. for 40 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=5:1) to obtain 3-((3-(2,2-difluoroethoxy)-5-nitrophenyl)difluoromethyl)benzonitrile (115.4 mg, 79%) as a yellow solid.

LC/MS ESI (+): 377 (M+Na)

¹H-NMR (300 MHz, DMSO-d₆): δ 8.27 (s, 1H), 8.00-8.06 (m, 3H), 7.96 (t, 1H, J=2.3 Hz), 7.70-7.75 (m, 2H), 6.43 (tt, 1H, J=54.2, 3.1 Hz), 4.58 (td, 2H, J=14.5, 3.1 Hz)

(h) Synthesis of 3-(difluoro(3-isobutoxy-5-nitrophenyl)methyl)benzonitrile

3-(Difluoro(3-hydroxy-5-nitrophenyl)methyl)benzonitrile (87.0 mg, 0.30 mmol) was dissolved in anhydrous DMF (5.0 mL), and 1-bromo-2-methylpropane (39.0 μL, 0.36 mmol) and K₂CO₃ (83.0 mg, 0.60 mmol) were added, followed by stirring at room temperature for 40 hours. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=5:1) to obtain 3-(difluoro(3-isobutoxy-5-nitrophenyl)methyl)benzonitrile (69.6 mg, 67%) as a white solid.

LC/MS ESI (+): 369 (M+Na)

¹H-NMR (300 MHz, DMSO-d₆): δ 8.26 (s, 1H), 8.03 (t, 2H, J=8.0 Hz), 7.95 (s, 1H), 7.83 (t, 1H, J=2.3 Hz), 7.73 (t, 1H, J=8.0 Hz), 7.63 (s, 1H), 3.93 (d, 2H, J=6.9 Hz), 1.97-2.10 (m, 1H), 0.99 (d, 6H, J=6.5 Hz)

(i) Synthesis of 3-((3-amino-5-(2,2-difluoroethoxy)phenyl)difluoromethyl)benzonitrile

3-((3-(2,2-Difluoroethoxy)-5-nitrophenyl)difluoromethyl)benzonitrile (114.0 mg, 0.33 mmol) was dissolved in a mixture of THF/MeOH/H₂O (6.6 mL, 1/1/0.1 v/v), and Zn (322.0 mg, 4.92 mmol) and NH₄Cl (88.0 mg, 1.64 mmol) were added at room temperature. The reaction mixture was ultrasonificated at 40° C. for 1.5 hours, cooled to room temperature, filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=5:1) to obtain 3-((3-amino-5-(2,2-difluoroethoxy)phenyl)difluoromethyl)benzonitrile (78.0 mg, 73%) as a white solid.

LC/MS ESI (+): 325 (M+1)

(j) Synthesis of N-(3-((3-cyanophenyl)difluoromethyl)-5-(2,2-difluoroethoxy)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(Methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (34.9 mg, 0.12 mmol), 3-((3-amino-5-(2,2-difluoroethoxy)phenyl)difluoromethyl)benzonitrile (39.0 mg, 0.12 mmol), HATU (54.8 mg, 0.14 mmol), and DIPEA (63.0 μL, 0.36 mmol) were dissolved in anhydrous DMF (1.0 mL), followed by stirring at 40° C. for 19 hours. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=20:1) to obtain N-(3-((3-cyanophenyl)difluoromethyl)-5-(2,2-difluoroethoxy)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (22.6 mg, 34%) as a white solid.

LC/MS ESI (+): 561 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.72 (s, 1H), 10.32 (s, 1H), 9.64 (s, 1H), 8.12 (s, 1H), 8.03 (d, 1H, J=8.0 Hz), 7.92 (d, 1H, J=8.0 Hz), 7.72-7.78 (m, 2H), 7.61-7.64 (m, 2H), 7.38 (s, 1H), 7.37 (s, 1H), 6.69-7.00 (m, 2H), 6.42 (t, 1H, J=54.6 Hz), 4.40 (td, 2H, J=14.1, 3.8 Hz), 2.93 (s, 3H)

Through the synthetic method according to Example 391, compounds of Example 392 and Example 393 were synthesized, and the data of each example are as follows.

TABLE 28 Ex. Compound Analysis data 392 N-(3-((3- LC/MS ESI (+): 553 (M + 1) cyanophenyl)difluoromethyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.71 (s, 1H), 10.27 (s, 5-isobutoxyphenyl)-6- 1H), 9.64 (s, 1H), 8.11 (s, 1H), 8.03 (d, 1H, J = 7.6 Hz), (methylsulfonamido)-1H- 7.90 (d, 1H, J = 8.0 Hz), 7.75 (t, 1H, J = 8.0 Hz), 7.61~7.65 indole-2-carboxamide (m, 2H), 7.55 (s, 1H), 7.38 (s, 2H), 6.98 (dd, 1H, J = 8.8, 1.9 Hz), 6.86 (s, 1H) 3.79 (d, 2H, J = 6.5 Hz), 2.94 (s, 3H), 2.04 (m, 1H), 1.00 (d, 6H, J = 6.9 Hz) 393 N-(3-(cyanomethoxy)-5- LC/MS ESI (+): 536 (M + 1) ((3- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.76 (s, 1H), 10.40 (s, cyanophenyl)difluoromethyl)phenyl)-6- 1H), 9.65 (s, 1H), 8.12 (s, 1H), 8.04 (d, 1H, J = 7.6 Hz), (methylsulfonamido)-1H- 7.92 (d, 1H, J = 8.0 Hz), 7.73~7.80 (m, 2H), 7.62~7.65 (m, indole-2-carboxamide 2H), 7.37~7.39 (m, 2H), 7.06 (s, 1H), 6.98 (dd, 1H, J = 8.8, 1.9 Hz), 5.25 (s, 2H), 2.94 (s, 3H)

Example 394 Synthesis of N-(3-((4-methoxyphenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of (4-methoxyphenyl)(3-nitrophenyl)sulfane

1-Bromo-3-nitrobenzene (500.0 mg, 2.48 mmol) was dissolved in 1,4-dioxane (10.0 mL), and 4-methoxybenzenethiol (383.0 mg, 2.73 mmol), Pd₂dba₃CHCl₃ (227.0 mg, 0.22 mmol), Xantphos (287.0 mg, 0.50 mmol), and DIPEA (0.9 mL, 5.46 mmol) were added, followed by refluxing at 100° C. for 15 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex) to obtain (4-methoxyphenyl)(3-nitrophenyl)sulfane (501.0 mg, 77%) as a yellow oil.

¹H-NMR (300 MHz, CDCl₃): δ 7.89-7.95 (m, 2H), 7.48 (d, 2H J=8.8 Hz), 7.36-7.40 (m, 2H), 6.97 (d, 2H, J=8.8 Hz), 3.86 (s, 3H).

(b) Synthesis of (1-((4-methoxyphenyl)sulfonyl)-3-nitrobenzene

(4-Methoxyphenyl)(3-nitrophenyl)sulfane (501.0 mg, 1.92 mmol) was dissolved in CH₂Cl₂ (10.0 mL), and mCPBA (994.0 mg, 5.76 mmol) was added, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with CH₂Cl₂. The organic extract was washed with sat. NaHCO₃ aqueous solution and brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to obtain (1-(4-methoxyphenyl)sulfonyl)-3-nitrobenzene (548.0 mg, 100%) as a yellow solid.

¹H-NMR (300 MHz, CDCl₃): δ 8.74 (s, 1H), 8.40 (d, 1H, J=8.0 Hz), 8.25 (d, 1H, J=7.6 Hz), 7.92 (d, 2H, J=9.2 Hz), 7.72 (t, 1H, J=8.0 Hz), 7.01 (d, 2H, J=9.2 Hz), 3.87 (s, 3H)

(c) Synthesis of 3-((4-methoxyphenyl)sulfonyl)aniline

(1-((4-Methoxyphenyl)sulfonyl)-3-nitrobenzene (548.0 mg, 1.92 mmol) was dissolved in MeOH (5.0 mL). Under an atmosphere of hydrogen gas, an excessive amount of Ra—Ni (0.2 g, 3.41 mmol) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 3-((4-methoxyphenyl)sulfonyl)aniline (285.0 mg, 56%) as a bright yellow solid.

LC/MS ESI (+): 264 (M+1)

(d) Synthesis of N-(3-((4-methoxyphenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(Methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (70.0 mg, 0.28 mmol), 3-((4-methoxyphenyl)sulfonyl)aniline (77.0 mg, 0.29 mmol), and HATU (128.0 mg, 0.34 mmol) were dissolved in anhydrous DMF (1.0 mL), and DIPEA (73.0 μL, 0.42 mmol) was added. After stirring at 80° C. for 15 hours, the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=95:5) to obtain N-(3-(4-methoxyphenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (1.2 mg, 1%) as a yellow solid.

LC/MS ESI (+): 500 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 10.53 (s, 1H), 9.69 (s, 1H), 8.42 (s, 1H), 8.10 (m, 1H), 7.81-7.92 (m, 2H) 7.57-7.69 (m, 3H), 7.36-7.56 (m, 2H), 7.11-7.23 (m, 2H), 6.98 (m, 1H), 3.89 (s, 3H), 2.98 (s, 3H)

Through the synthetic method according to Example 394, compounds from Example 395 to Example 399 were synthesized, and the data of each example are as follows.

TABLE 29 Ex. Compound Analysis data 395 6-(methylsulfonamido)-N-(3- LC/MS ESI (+): 470 (M + 1) (phenylsulfonyl)phenyl)-1H- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.77 (s, 1H), indole-2-carboxamide 10.52 (s, 1H), 9.66 (s, 1H), 8.45 (s, 1H), 8.11 (m, 1H), 7.95~7.97 (m, 2H) 7.59~7.74 (m, 6H), 7.40 (m, 2H), 6.97 (m, 1H), 2.45 (s, 3H) 396 6-(methylsulfonamido)-N-(3- LC/MS ESI (+): 554 (M + 1) ((3- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), (trifluoromethoxy)phenyl)sulfonyl)phenyl)- 10.54 (s, 1H), 9.65 (s, 1H), 8.45 (s, 1H), 8.14 (m, 1H-indole-2- 1H), 8.00 (m, 1H), 7.92 (s, 1H), 7.73~7.82 (m, carboxamide 3H), 7.62~7.65 (m, 2H), 7.39~7.42 (m, 2H), 6.98 (m, 1H), 2.94 (s, 3H) 397 N-(3-methoxy-5-((3- LC/MS ESI (+): 584 (M + 1) (trifluoromethoxy)phenyl)sulfonyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 6- 10.50 (s, 1H), 9.68 (s, 1H), 7.97~8.06 (m, 3H), (methylsulfonamido)-1H- 7.79~7.80 (m, 3H) 7.64 (d, 1H, J = 8.1 Hz), indole-2-carboxamide 7.39~7.41 (m, 2H), 7.27 (s, 1H), 7.00 (m, 1H), 3.86 (s, 3H), 2.94 (s, 3H) 398 6-(methylsulfonamido)-N-(3- LC/MS ESI (+): 622 (M + 1) ((3- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.81 (s, 1H), (trifluoromethoxy)phenyl)sulfonyl)- 10.81 (s, 1H), 9.68 (brs, 1H), 8.75 (s, 1H), 8.55 (s, 5- 1H), 8.07~8.17 (m, 3H) 7.78~7.92 (m, 2H), 7.67 (d, (trifluoromethyl)phenyl)-1H- 1H, J = 8.4 Hz), 7.42 (d, 2H, J = 10.7 Hz), 6.99 (dd, 1H, indole-2-carboxamide J = 8.4, 1.5 Hz), 2.95 (s, 3H) 399 N-(3-cyano-5-((3- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.81 (s, 1H), (trifluoromethoxy)phenyl)sulfonyl)phenyl)- 10.78 (s, 1H), 9.89 (brs, 1H), 8.68 (s, 1H), 8.55 (s, 6- 1H), 8.32 (s, 1H), 8.04~8.10 (m, 2H), 7.81~7.84 (m, (methylsulfonamido)-1H- 2H), 7.66 (d, 1H, J = 8.5 Hz), 7.42 (s, 1H), 7.39 (s, indole-2-carboxamide 1H), 6.97~7.00 (m, 1H), 2.94 (s, 3H)

Example 400 Synthesis of N-(3-isobutoxy-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 3-nitro-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenol

1-Methoxy-3-nitro-5-((3-(trifluoromethoxy)phenyl)sulfonyl)benz ene (0.3 g, 0.80 mmol) was dissolved in CH₂Cl₂ (5.0 mL), and 1.0 M solution of BBr₃ in CH₂Cl₂ (8.0 mL, 8.00 mmol) was added at 0° C. After stirring at room temperature for 15 hours, the reaction mixture was extracted with CH₂Cl₂. The organic extract was washed with sat. NaHCO₃ aqueous solution and brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain 3-nitro-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenol (213.0 mg, 68%) as a pink amorphous solid.

¹H-NMR (300 MHz, CDCl₃): δ 8.30 (t, 1H, J=1.9 Hz), 7.89-7.93 (m, 2H), 7.82 (s, 1H), 7.75 (dd, 1H, J=2.3, 1.9 Hz), 7.63 (t, 1H, J=8.4 Hz), 7.50 (d, 1H, J=8.4 Hz), 6.83 (s, 1H).

(b) Synthesis of 1-isobutoxy-3-nitro-5-((3-(trifluoromethoxy)phenyl)sulfonyl)benzene

3-Nitro-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenol (100.0 mg, 0.28 mmol) was dissolved in THF (2.0 mL), and 2-methylpropan-1-ol (21.0 mg, 0.28 mmol), DIAD (54.0 μL, 0.28 mmol), and PPh₃ (73.0 mg, 0.28 mmol) were added, followed by stirring at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=3:1) to obtain 1-isobutoxy-3-nitro-5-((3-(trifluoromethoxy)phenyl)sulfonyl)benzene (54.0 mg, 46%) as a yellow oil.

LC/MS ESI (+): 420 (M+1)

(c) Synthesis of 3-isobutoxy-5-(3-(trifluoromethoxy)phenylsulfonyl)aniline

1-Isobutoxy-3-nitro-5-((3-(trifluoromethoxy)phenyl)sulfonyl)benzene (54.0 mg, 0.13 mmol) was dissolved in a mixture of THF/MeOH/H₂O (1.6 mL, 10/5/0.1 v/v), and Zn (85.0 mg, 1.30 mmol) and NH₄Cl (20.9 mg, 0.39 mmol) were added. The reaction mixture was ultrasonificated at 40° C. for 1 hour. The reaction mixture was filtered through Celite and extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=60:40) to obtain 3-isobutoxy-5-(3-(trifluoromethoxy)phenyl sulfonyl)aniline (17.2 mg, 34%) as a yellow oil.

LC/MS ESI (+): 390 (M+1)

(d) Synthesis of N-(3-isobutoxy-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(Methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (17.2 mg, 0.04 mmol), 3-isobutoxy-5-((3-(trifluoromethoxy)phenyl)sulfonyl)aniline (13.5 mg, 0.05 mmol), and HATU (21.7 mg, 0.06 mmol) were dissolved in anhydrous DMF (3.0 mL), and DIPEA (11.5 μL, 0.07 mmol) was added. After stirring at 50° C. for 15 hours, the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH₂Cl₂:MeOH=96:4) to obtain N-(3-isobutoxy-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (1.9 mg, 7%) as a white solid.

LC/MS ESI (+): 626 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.76 (brs, 1H), 10.46 (brs, 1H), 9.67 (brs, 1H), 7.97-8.05 (m, 3H), 7.75-7.84 (m, 3H), 7.64 (d, 1H, J=8.4 Hz), 7.40 (m, 2H), 7.25 (m, 1H), 7.00 (dd, 1H, J=8.4, 1.5 Hz), 3.84 (d, 2H, J=6.5 Hz), 2.95 (s, 3H), 2.02-2.06 (m, 1H), 0.99 (d, 6H, J=6.9 Hz)

Through the synthetic method according to Example 400, a compound of Example 401 was synthesized, and the data of the example are as follows.

TABLE 30 Ex. Compound Analysis data 401 N-(3-(2,2-difluoroethoxy)-5- LC/MS ESI (+): 634 (M + 1) ((3- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), (trifluoromethoxy)phenyl)sulfonyl)phenyl)- 10.51 (s, 1H), 9.67 (m, 1H), 8.03~8.09 (m, 3H), 6- 7.76~7.87 (m, 3H), 7.65 (d, 1H, J = 8.4 Hz), 7.39~7.41 (m, 3H), (methylsulfonamido)-1H- 7.00 (dd, 1H, J = 9.0, 1.8 Hz), 6.43 (t, 1H, J = 71.7 Hz), indole-2-carboxamide 4.47 (td, 2H, J = 14.7, 3.3 Hz), 2.94 (s, 3H)

Example 402 Synthesis of N-(3-((3-cyanophenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of tert-butyl(3-mercaptophenyl)carbamate

3-Aminobenzenethiol (456.2 mg, 3.64 mmol) and Boc₂O (835.0 mg, 3.83 mmol) were dissolved in acetone (5.0 mL) at 0° C., and 5% NaHCO₃ aqueous solution (2.5 mL) was slowly added. The mixture was stirred at 0° C. for 30 minutes and at room temperature for 48 hours. The reaction mixture was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=5:1) to obtain tert-butyl(3-mercaptophenyl)carbamate (297.0 mg, 36%) as a white solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 9.35 (s, 1H), 7.48 (s, 1H), 7.07-7.12 (m, 2H), 6.87 (dt, 1H, J=6.9, 1.9 Hz), 5.39 (s, 1H), 1.46 (s, 9H)

(b) Synthesis of tert-butyl (3-((3-cyanophenyl)thio)phenyl)carbamate

tert-Butyl(3-mercaptophenyl)carbamate (100.0 mg, 0.37 mmol) was dissolved in 1,4-dioxane (3.0 mL), and 3-bromobenzonitrile (67.0 mg, 0.37 mmol) and Pd₂dba₃ (38.0 mg, 0.04 mmol), Xantphos (42.6 mg, 0.07 mmol), and DIPEA (128.0 μL, 0.74 mmol) were added, followed by refluxing at 100° C. for 15 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=5:1) to obtain tert-butyl (3-((3-cyanophenyl)thio)phenyl)carbamate (100.8 mg, 84%) as a yellow oil.

¹H-NMR (500 MHz, DMSO-d₆): δ 9.48 (s, 1H), 7.71-7.73 (m, 1H), 7.67 (s, 1H), 7.59 (s, 1H), 7.52-7.55 (m, 2H), 7.47 (d, 1H, J=8.4 Hz), 7.33 (t, 1H, J=7.6 Hz), 7.03 (d, 1H, J=8.0 Hz), 1.45 (s, 9H)

(c) Synthesis of tert-butyl (3-((3-cyanophenyl)sulfonyl)phenyl)carbamate

tert-Butyl (3-((3-cyanophenyl)thio)phenyl)carbamate (618.0 mg, 1.89 mmol) was dissolved in CH₂Cl₂ (10.0 mL), and mCPBA (1.0 g, 5.68 mmol) was added, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, n-Hex:EtOAc=1:1) to obtain tert-butyl (3-((3-cyanophenyl)sulfonyl)phenyl)carbamate (545.0 mg, 80%) as a white solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 9.78 (s, 1H), 8.42 (s, 1H), 8.16-8.23 (m, 3H), 7.83 (t, 1H, J=7.6 Hz), 7.60-7.67 (m, 2H), 7.52 (t, 1H, J=7.6 Hz), 1.47 (s, 9H)

(d) Synthesis of 3-((3-aminophenyl)sulfonyl)benzonitrile

tert-Butyl (3-((3-cyanophenyl)sulfonyl)phenyl)carbamate (546.0 mg, 1.52 mmol) was dissolved in CH₂Cl₂ (5.0 mL), and TFA (2.5 mL, 32.65 mmol) was added, followed by stirring at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain 3-((3-aminophenyl)sulfonyl)benzonitrile (240.0 mg, 61%) as a yellow solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 8.37 (t, 1H, J=1.5 Hz), 8.14-8.19 (m, 2H), 7.82 (t, 1H, J=8.0 Hz), 7.23 (t, 1H, J=8.0 Hz), 7.05-7.11 (m, 2H), 6.80 (dd, 1H, J=8.0, 2.3 Hz), 5.71 (s, 2H)

(e) Synthesis of N-(3-((3-cyanophenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(Methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (70.0 mg, 0.28 mmol), 3-((3-aminophenyl)sulfonyl)benzonitrile (59.1 mg, 0.23 mmol), and HATU (104.6 mg, 0.28 mmol) were dissolved in anhydrous DMF (1.0 mL), and DIPEA (58.0 μL, 0.33 mmol) was added. After stirring at 60° C. for 13 hours, the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=95:5) to obtain N-(3-((3-cyanophenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (14.3 mg, 13%) as an off-white solid.

LC/MS ESI (+): 495 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 10.54 (s, 1H), 9.67 (s, 1H), 8.48 (s, 1H), 8.47 (s, 1H), 8.27 (d, 1H, J=8.0 Hz), 8.20 (d, 1H, J=7.6 Hz), 8.14 (d, 1H, J=7.6 Hz), 7.86 (t, 1H, J=8.0 Hz), 7.76 (d, 1H, J=7.6 Hz), 7.65 (t, 1H, J=7.6 Hz), 7.65 (d, 1H, J=8.4 Hz), 7.42 (s, 1H), 7.39 (s, 1H), 6.99 (dd, 1H, J=8.4, 1.5 Hz), 2.94 (s, 3H)

Through the synthetic method according to Example 402, compounds from Example 403 to Example 417 were synthesized, and the data of each example are as follows.

TABLE 31 Ex. Compound Analysis data 403 6-(methylsulfonamido)-N- LC/MS ESI (+): 471 (M + 1) (3-(pyridin-2- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.74 (s, 1H), 10.54 (s, ylsulfonyl)phenyl)-1H- 1H), 9.66 (s, 1H), 8.73 (d, 1H, J = 4.6 Hz), 8.48 (s, 1H), indole-2-carboxamide 8.15~8.26 (m, 3H), 7.61~7.73 (m, 4H), 7.43 (s, 1H), 7.38 (s, 1H), 6.98 (d, 1H, J = 8.4 Hz), 2.93 (s, 3H) 404 6-(methylsulfonamido)-N- LC/MS ESI (+): 471 (M + 1) (3-(pyridin-3- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 10.54 (s, ylsulfonyl)phenyl)-1H- 1H), 9.66 (s, 1H), 9.14 (d, 1H, J = 2.3 Hz), 8.89 (d, 1H, indole-2-carboxamide J = 4.2 Hz), 8.49 (s, 1H), 8.36 (d, 1H, J = 8.0 Hz), 8.14 (d, 1H, J = 7.3 Hz), 7.63~7.77 (m, 4H), 7.42 (s, 1H), 7.39 (s, 1H), 6.99 (dd, 1H, J = 8.4, 1.5 Hz), 2.94 (s, 3H) 405 N-(3-((3- LC/MS ESI (+): 504 (M + 1) chlorophenyl)sulfonyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 10.53 (s, 6- 1H), 9.66 (s, 1H), 8.47 (m, 1H), 8.14 (m, 1H), 7.98 (s, (methylsulfonamido)-1H- 1H), 7.93 (d, 1H, J = 7.8 Hz), 7.62~7.83 (m, 5H), indole-2-carboxamide 7.32~7.45 (m, 2H), 6.99 (dd, 1H, J = 8.4, 1.7 Hz), 2.95 (s, 3H) 406 N-(3-((6-cyanopyridin-2- LC/MS ESI (+): 496 (M + 1) yl)sulfonyl)phenyl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.77 (s, 1H), 10.58 (s, (methylsulfonamido)-1H- 1H), 9.66 (s, 1H), 8.49~8.54 (m, 2H), 8.43 (d, 1H, indole-2-carboxamide J = 7.8 Hz), 8.33 (m, 1H), 8.24 (m, 1H), 7.53~7.73 (m, 3H), 7.39~7.44 (m, 2H), 6.99 (dd, 1H, J = 8.6, 1.7 Hz), 2.95 (s, 3H) 407 N-(3-((5-methoxypyridin- LC/MS ESI (+): 501 (M + 1) 3-yl)sulfonyl)phenyl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 10.54 (s, (methylsulfonamido)-1H- 1H), 9.66 (s, 1H), 8.70 (d, 1H, J = 1.9 Hz), 8.60 (d, 1H, indole-2-carboxamide J = 2.9 Hz), 8.49 (m, 1H), 8.14 (m, 1H), 7.79~7.82 (m, 2H), 7.62~7.68 (m, 2H), 7.37~7.44 (m, 2H), 6.99 (dd, 1H, J = 8.8, 1.9 Hz), 3.93 (s, 3H), 2.95 (s, 3H) 408 N-(3-((6-methoxypyridin- LC/MS ESI (+): 501 (M + 1) 2-yl)sulfonyl)phenyl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.75 (s, 1H), 10.53 (s, (methylsulfonamido)-1H- 1H), 9.65 (s, 1H), 8.56 (m, 1H), 8.16 (m, 1H), 8.02 (m, indole-2-carboxamide 1H), 7.79 (d, 1H, J = 7.4 Hz), 7.61~7.73 (m, 3H), 7.39~7.43 (m, 2H), 7.13 (d, 1H, J = 8.4 Hz), 6.99 (dd, 1H, J = 8.4, 1.1 Hz), 3.83 (s, 3H), 2.95 (s, 3H) 409 N-(3-(benzo[b]thiophen-5- LC/MS ESI (+): 526 (M + 1) ylsulfonyl)phenyl)-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.76 (s, 1H), 10.50 (s, (methylsulfonamido)-1H- 1H), 9.64 (brs, 1H), 8.56 (s, 1H), 8.48 (s, 1H), 8.29 (d, indole-2-carboxamide 1H, J = 8.4 Hz), 8.08 (d, 1H, J = 7.6 Hz), 8.01 (d, 1H, J = 5.3 Hz), 7.83 (dd, 1H, J = 8.4, 1.5 Hz), 7.69 (d, 2H, J = 5.7 Hz), 7.63 (dd, 2H, J = 8.0, 3.8 Hz), 7.39 (d, 2H, J = 7.3 Hz), 6.99 (dd, 1H, J = 8.4, 1.9 Hz), 2.94 (s, 3H) 410 N-(3-((2- LC/MS ESI (+): 541 (M + 1) methylbenzo[d]thiazol-6- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 10.53 (s, yl)sulfonyl)phenyl)-6- 1H), 9.67 (brs, 1H), 8.82 (s, 1H), 8.49 (s, 1H), (methylsulfonamido)-1H- 8.09~8.14 (m, 1H), 7.98 (dd, 1H, J = 8.8, 1.9 Hz), 7.61~7.74 (m, 5H), indole-2-carboxamide 7.41 (d, 1H, J = 8.4 Hz), 7.01 (dd, 1H, J = 8.4, 1.5 Hz), 2.95 (s, 3H), 2.86 (s, 3H) 411 N-(3-((3-cyano-5- LC/MS ESI (+): 525 (M + 1) methoxyphenyl)sulfonyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 10.53 (s, 6- 1H), 9.66 (brs, 1H), 8.46 (s, 1H), 8.15 (d, 1H, J = 8.0 Hz), (methylsulfonamido)-1H- 7.99 (s, 1H), 7.83 (s, 1H) 7.78 (d, 1H, J = 7.6 Hz), indole-2-carboxamide 7.70~7.73 (m, 1H), 7.62~7.67 (m, 2H), 7.41 (d, 2H, J = 8.8 Hz), 7.00 (dd, 1H, J = 8.4, 1.9 Hz), 3.91 (s, 3H), 2.95 (s, 3H) 412 N-(3-((3- LC/MS ESI (+): 509 (M + 1) (cyanomethyl)phenyl)sulfonyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.77 (s, 1H), 10.54 (s, 6- 1H), 9.67 (s, 1H), 8.46 (s, 1H), 8.13 (d, 1H, J = 7.8 Hz), (methylsulfonamido)-1H- 7.91~7.96 (m, 2H), 7.61~7.70 (m, 5H), 7.38~7.42 (m, indole-2-carboxamide 2H), 6.98 (d, 1H, J = 8.4 Hz), 4.21 (s, 2H), 2.94 (s, 3H) 413 6-(methylsulfonamido)-N- LC/MS ESI (+): 538 (M + 1) (3-((4-oxo-4H-chromen-7- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 10.53 (s, yl)sulfonyl)phenyl)-1H- 1H), 9.65 (brs, 1H), 8.52 (d, 1H, J = 2.3 Hz), 8.48 (t, 1H, indole-2-carboxamide J = 1.9 Hz), 8.38 (d, 1H, J = 6.1 Hz), 8.29 (dd, 1H, J = 8.8, 2.3 Hz), 8.14~8.17 (m, 1H), 7.91 (d, 1H, J = 8.8 Hz), 7.73~7.76 (m, 1H), 7.61~7.67 (m, 2H), 7.40 (dd, 2H, J = 8.8, 1.5 Hz), 7.00 (dd, 1H, J = 8.4, 1.9 Hz), 6.48 (d, 1H, J = 6.1 Hz), 2.94 (s, 3H) 414 N-(3-((3- LC/MS ESI (+): 548 (M + 1) bromophenyl)sulfonyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 10.53 (s, 6- 1H), 9.66 (s, 1H), 8.46 (s, 1H), 8.14 (d, 1H, J = 8.0 Hz), (methylsulfonamido)-1H- 8.09 (s, 1H), 7.93~7.98 (m, 2H), 7.74 (d, 1H, J = 8.4 Hz), indole-2-carboxamide 7.59~7.67 (m, 3H), 7.42 (s, 1H), 7.40 (s, 1H), 6.99 (d, 1H, J = 9.2 Hz), 2.95 (s, 3H) 415 N-(3-((3- LC/MS ESI (+): 485 (M + 1) aminophenyl)sulfonyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.76 (s, 1H), 10.52 (s, 6- 1H), 9.65 (brs, 1H), 8.42 (s, 1H), 8.07~8.11 (m, 1H), (methylsulfonamido)-1H- 7.56~7.66 (m, 3H), 7.41 (d, 2H, J = 10.3 Hz), 7.23 (t, 1H, indole-2-carboxamide J = 8.0 Hz), 6.97~7.09 (m, 1H), 6.97~7.02 (m, 2H), 6.78 (dd, 1H, J = 8.0, 2.3 Hz), 5.70 (brs, 2H), 2.95 (s, 3H) 416 N-(3-((3- LC/MS ESI (+): 494 (M + 1) ethynylphenyl)sulfonyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.78 (s, 1H), 10.52 (s, 6- 1H), 9.66 (s, 1H), 8.46 (s, 1H), 8.14 (d, 1H, J = 8.4 Hz), (methylsulfonamido)-1H- 7.97~7.99 (m, 2H), 7.81 (d, 1H, J = 7.6 Hz), 7.61~7.73 (m, indole-2-carboxamide 4H), 7.42 (s, 1H), 7.39 (s, 1H), 6.99 (dd, 1H, J = 8.4, 1.9 Hz), 4.48 (s, 1H), 2.95 (s, 3H) 417 N-(3-((3-cyano-5- LC/MS ESI (+): 511 (M + 1) hydroxyphenyl)sulfonyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.79 (s, 1H), 6- 11.30 (brs, 1H), 10.54 (s, 1H), 9.66 (brs, 1H), 8.45 (s, 1H), (methylsulfonamido)-1H- 8.15 (d, 1H, J = 8.9 Hz), 7.61~7.77 (m, 4H), 7.52 (s, 1H), indole-2-carboxamide 7.39~7.43 (m, 3H), 6.99 (dd, 1H, J = 8.4, 2.1 Hz), 2.95 (s, 3H)

Example 418 Synthesis of N-(3-bromo-5-((7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 2-((3-bromo-5-nitrophenyl)sulfonyl)-7-fluoro-1,2,3,4-tetrahydroisoquinoline

7-Fluoro-1,2,3,4-tetrahydroisoquinoline (100.0 mg, 0.66 mmol) was dissolved in CH₂Cl₂ (5.0 mL), and DIPEA (172.0 μL, 0.99 mmol) and 3-bromo-5-nitrobenzenesulfonyl chloride (198.0 mg, 0.66 mmol) were added, followed by stirring for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, n-Hex:CH₂Cl₂=1:3) to obtain 2-((3-bromo-5-nitrophenyl)sulfonyl)-7-fluoro-1,2,3,4-tetrahydroisoquinoline (270.0 mg, 98%) as a white solid.

LC/MS ESI (+): 415 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 8.55-8.57 (m, 2H), 8.26 (d, 1H, J=1.6 Hz), 7.06 (dd, 1H, J=8.4, 5.2 Hz), 6.89 (td, 1H, J=8.4, 2.8 Hz), 6.80 (dd, 1H, J=8.8, 2.8 Hz), 4.37 (s, 2H), 3.51 (t, 2H, J=6.0 Hz), 2.91 (t, 2H, J=6.0 Hz)

(b) Synthesis of 3-bromo-5-((7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)aniline

The synthesis procedure of Intermediate 40 was repeated except for using 2-((3-bromo-5-nitrophenyl)sulfonyl)-7-fluoro-1,2,3,4-tetrahydroisoquinoline (130.0 mg, 0.31 mmol) to obtain 3-bromo-5-((7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)aniline (105.0 mg, 87%).

LC/MS ESI (+): 385 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.28 (s, 1H), 7.06 (dd, 1H, J=8.4, 6.0 Hz), 7.00 (s, 1H), 6.98 (s, 1H), 6.87 (td, 1H, J=8.4, 2.4 Hz), 6.76 (dd, 1H, J=9.6, 6.4 Hz), 4.26 (s, 2H), 3.99 (brs, 2H), 3.39 (t, 2H, J=6.0 Hz), 2.90 (t, 2H, J=6.0 Hz)

(c) Synthesis of N-(3-bromo-5-((7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-bromo-5-((7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)aniline (70.9 mg, 0.31 mmol) to obtain N-(3-bromo-5-((7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (32.8 mg, 28%).

LC/MS ESI (+): 638 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.88 (s, 1H), 9.89 (s, 1H), 8.34 (s, 2H), 8.27 (t, 1H, J=1.6 Hz), 8.05 (d, 1H, J=8.8 Hz), 7.83 (d, 1H, J=2.0 Hz), 7.67 (t, 1H, J=1.6 Hz), 7.39 (dd, 1H, J=8.8, 2.0 Hz), 7.15 (dd, 1H, J=8.4, 6.0 Hz), 7.08 (dd, 1H, J=10.0, 2.8 Hz), 6.99 (dd, 1H, J=8.4, 2.8 Hz), 4.33 (s, 2H), 3.42 (t, 2H, J=6.0 Hz), 3.03 (s, 3H), 2.84 (t, 2H, J=6.0 Hz)

Example 419 Synthesis of N-(3-bromo-5-((5,7-difluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 418 was repeated except for using 5,7-difluoro-1,2,3,4-tetrahydroisoquinoline (100.0 mg, 0.58 mmol) to obtain N-(3-bromo-5-((5,7-difluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (12.7 mg).

LC/MS ESI (+): 656 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 9.91 (s, 1H), 8.34-8.35 (m, 2H), 8.29 (s, 1H), 8.07 (d, 1H, J=8.4 Hz), 7.85 (d, 1H, J=2.0 Hz), 7.68 (t, 1H, J=1.6 Hz), 7.40 (dd, 1H, J=8.8, 2.0 Hz), 7.06 (m, 2H), 4.37 (s, 2H), 3.48 (t, 2H, J=6.0 Hz), 3.04 (s, 3H), 2.76 (t, 2H, J=6.0 Hz)

Example 420 Synthesis of N-(3-bromo-5-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 418 was repeated except for using 4,4-difluoropiperidine (58.0 mg, 0.33 mmol) to obtain N-(3-bromo-5-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (30.0 mg).

LC/MS ESI (+): 608 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.91 (s, 1H), 9.90 (brs, 1H), 8.39 (s, 1H), 8.34 (s, 1H), 8.22 (s, 1H), 8.04 (d, 1H, J=8.7 Hz), 7.82 (s, 1H), 7.66 (s, 1H), 7.38 (dd, 1H, J=8.7, 2.1 Hz), 3.15-3.18 (m, 4H), 3.02 (s, 3H), 2.05-2.15 (m, 4H)

Example 421 Synthesis of 5-(methylsulfonamido)-N-(3-(1-phenylcyclopropyl)phenyl)benzo[b]thiophene-2-carboxamide (a) Synthesis of 1-nitro-3-(1-phenylvinyl)benzene

Bromo(methyl)triphenylphosphorane (1.2 g, 4.40 mmol) was dissolved in THF (7.6 mL), and n-BuLi (2.8 mL, 4.40 mmol) was slowly added at 0° C., followed by stirring for 30 minutes. The reaction mixture was slowly added to a mixture of (3-nitrophenyl)(phenyl)methanone (500.0 mg, 2.20 mmol) dissolved in THF (1.8 mL) at 0° C. After stirring at room temperature for 12 hours, the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:CH₂Cl₂=2:1) to obtain 1-nitro-3-(1-phenylvinyl)benzene (321.0 mg, 65%) as a yellow solid.

¹H-NMR (300 MHz, CDCl₃): δ 8.22 (s, 1H), 8.18 (d, 1H, J=7.3 Hz), 7.66 (d, 1H, J=7.7 Hz), 7.51-7.53 (m, 1H), 7.36-7.39 (m, 3H), 7.28-7.36 (m, 2H), 5.61 (s, 1H), 5.57 (s, 1H)

(b) Synthesis of 1-nitro-3-(1-phenylcyclopropyl)benzene

1-Nitro-3-(1-phenylvinyl)benzene (319.0 mg, 1.42 mmol) and CH₂I₂ (1.1 mL, 14.20 mmol) were dissolved in 1,2-dichloroethane, and 1.0 M solution of Et₂Zn in hexane (7.1 mL, 7.08 mmol) was slowly added, followed by stirring at room temperature for 12 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain a mixture of yellow solid compounds 1-nitro-3-(1-phenylvinyl)benzene and 1-nitro-3-(1-phenylcyclopropyl)benzene (129.0 mg).

(c) Synthesis of 1-(2,2-dibromo-1-phenylcyclopropyl)-3-nitrobenzene

1-Nitro-3-(1-phenylvinyl)benzene (135.0 mg, 0.60 mmol), CHBr₃ (71.2 μL, 0.82 mmol), and benzyltriethylammonium chloride (24.6 mg, 0.11 mmol) were dissolved in 1,2-dichloroethane (0.6 mL), and NaOH (910.0 mg, 22.8 mmol) dissolved in H₂O (0.9 mL) was added. After stirring at 40° C. for 24 hours, the reaction mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 1-(2,2-dibromo-1-phenylcyclopropyl)-3-nitrobenzene (151.6 mg, 63%) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ 8.34-8.35 (m, 1H), 8.09-8.13 (m, 1H), 7.88-7.92 (m, 1H), 7.49-7.54 (m, 3H), 7.33-7.39 (m, 2H), 7.25-7.31 (m, 1H), 2.58 (d, 1H, J=8.0 Hz), 2.52 (d, 1H, J=8.0 Hz)

(d) Synthesis of 3-(1-phenylcyclopropyl)aniline

The mixture of 1-nitro-3-(1-phenylvinyl)benzene and 1-nitro-3-(1-phenylcyclopropyl)benzene (129.0 mg), Zn (562.0 mg), and NH₄Cl (153.0 mg) were dissolved in a mixture of THF/MeOH/H₂O (12.0 mL, 1/1/0.5 v/v), and ultrasonificated at 40° C. for 3 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:CH₂Cl₂=1:1) to obtain a mixture of white solid compounds of 3-(1-phenylvinyl)aniline and 3-(1-phenylcyclopropyl)aniline (59.0 mg).

LC/MS ESI (+): 210 (M+1)

(e) Synthesis of 5-(methylsulfonamido)-N-(3-(1-phenylcyclopropyl)phenyl)benzo[b]thiophene-2-carboxamide

5-(Methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (81.0 mg, 0.30 mmol), the mixture of 3-(1-phenylvinyl)aniline and 3-(1-phenylcyclopropyl)aniline (58.0 mg), and HATU (125.0 mg, 0.33 mmol) were dissolved in anhydrous DMF (3.0 mL), and DIPEA (78.0 μL, 0.45 mmol) was added. After stirring at 40° C. for 24 hours, the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was first purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:2). The residue was secondly purified by reversed-phase column chromatography (C18-silica gel, CH₃CN:H₂O=52:48) to obtain 5-(methylsulfonamido)-N-(3-(1-phenylcyclopropyl)phenyl)benzo[b]thiophene-2-carboxamide (8.5 mg, 7%) as a white solid.

LC/MS ESI (+): 463 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 10.41 (s, 1H), 9.87 (s, 1H), 8.29 (s, 1H), 8.01 (d, 1H, J=8.8 Hz), 7.78 (d, 1H, J=2.2 Hz), 7.63-7.66 (m, 2H), 7.35 (dd, 1H, J=8.8, 2.2 Hz), 7.16-7.33 (m, 6H), 7.01 (d, 1H, J=7.7 Hz), 3.01 (s, 3H), 1.27 (s, 4H)

Through the synthetic method according to Example 421, compounds from Example 422 to Example 433 were synthesized, and the data of each example are as follows.

TABLE 32 Ex. Compound Analysis data 422 6-(methylsulfonamido)-N-(3- LC/MS ESI (+): 446 (M + 1) (1-phenylcyclopropyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.66 (s, 1H), 1H-indole-2-carboxamide 10.08 (s, 1H), 9.59 (s, 1H), 7.70 (d, 1H, J = 8.4 Hz), 7.67 (s, 1H), 7.61 (d, 1H, J = 8.4 Hz), 7.37 (dd, 2H, J = 4.6, 2.3 Hz), 7.19~7.32 (m, 6H), 6.96~7.00 (m, 2H), 2.94 (s, 3H), 1.27 (s, 4H) 423 5-(methylsulfonamido)-N-(3- LC/MS ESI (+): 449 (M + 1) (1- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.48 (s, 1H), phenylvinyl)phenyl)benzo[b]thiophene- 9.85 (s, 1H), 8.29 (s, 1H), 8.01 (d, 1H, J = 8.8 Hz), 2-carboxamide 7.84 (d, 1H, J = 8.1 Hz), 7.77 (s, 1H), 7.67 (s, 1H), 7.33~7.43 (m, 7H), 7.10 (d, 1H, J = 7.7 Hz), 5.53 (s, 1H), 5.50 (s, 1H), 3.01 (s, 3H) 424 N-(3-(1-(4- LC/MS ESI (+): 481 (M + 1) fluorophenyl)cyclopropyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.39 (s, 1H), 5- 9.85 (s, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.8 Hz), (methylsulfonamido)benzo[b]thiophene- 7.79 (d, 1H, J = 1.9 Hz), 7.63~7.65 (m, 2H), 7.35 (dd, 2-carboxamide 1H, J = 8.8, 1.9 Hz), 7.26~7.31 (m, 3H), 7.09~7.15 (m, 2H), 6.99 (d, 1H, J = 7.3 Hz), 3.01 (s, 3H), 1.26 (s, 4H) 425 N-(3-(1-(4- LC/MS ESI (+): 464 (M + 1) fluorophenyl)cyclopropyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.66 (s, 1H), 6-(methylsulfonamido)-1H- 10.07 (s, 1H), 9.58 (s, 1H), 7.69 (d, 1H, J = 8.0 Hz), indole-2-carboxamide 7.64 (s, 1H), 7.60 (d, 1H, J = 8.8 Hz), 7.38 (s, 1H), 7.36 (s, 1H), 7.24~7.32 (m, 3H), 7.08~7.14 (m, 2H), 6.93~7.00 (m, 2H), 2.94 (s, 3H), 1.26 (s, 4H) 426 N-(3-bromo-5-(1-(2,4- LC/MS ESI (+): 577 (M + 1) difluorophenyl)cyclopropyl)phenyl)- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.49 (s, 1H), 5- 9.85 (s, 1H), 8.27 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), (methylsulfonamido)benzo[b]thiophene- 7.94 (s, 1H), 7.80 (s, 1H), 7.56~7.64 (m, 1H), 2-carboxamide 7.49 (s, 1H), 7.36 (dd, 1H, J = 8.8, 1.9 Hz), 7.19~7.26 (m, 1H), 7.11 (d, 1H, J = 7.3 Hz), 7.03 (s, 1H), 3.01 (s, 3H), 1.23~1.38 (m, 4H) 427 N-(3-methoxy-5-(1-(3- LC/MS ESI (+): 607 (M + 1) methoxy-5- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.37 (s, 1H), (trifluoromethoxy)phenyl)cyclopropyl)phenyl)- 9.87 (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.4 Hz), 5- 7.78 (d, 1H, J = 1.9 Hz), 7.34~7.38 (m, 2H), 7.27 (s, (methylsulfonamido)benzo[b]thiophene- 1H), 6.77~6.80 (m, 2H), 6.72 (s, 1H), 6.60 (s, 1H), 2-carboxamide 3.77 (s, 3H), 3.74 (s, 3H), 3.01 (s, 3H), 1.29~1.30 (m, 4H) 428 N-(3-(difluoromethoxy)-5-(1- LC/MS ESI (+): 530 (M + 1) (4- ¹H-NMR (300 MHz, DMSO-d₆): δ 11.72 (s, 1H), fluorophenyl)cyclopropyl)phenyl)- 10.23 (s, 1H), 9.62 (s, 1H), 7.65 (s, 1H), 7.62 (d, 1H, 6-(methylsulfonamido)-1H- J = 9.2 Hz) 7.48 (s, 1H), 7.38 (s, 2H), 7.30~7.34 (m, indole-2-carboxamide 2H + 0.3H), 7.11~7.21 (m, 2H + 0.4H), 6.98 (d, 1H + 0.3H, J = 8.0 Hz), 6.71 (s, 1H), 2.93 (s, 3H), 1.29 (s, 4H) 429 N-(3-(difluoromethoxy)-5-(1- LC/MS ESI (+): 547 (M + 1) (4- ¹H-NMR (300 MHz, DMSO-d₆): δ 10.51 (s, 1H), fluorophenyl)cyclopropyl)phenyl)- 9.83 (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.4 Hz), 5- 7.79 (s, 1H), 7.59 (s, 1H), 7.46 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.30~7.38 (m, 3H), 7.21 (t, 1H, J = 73.6 Hz), 7.11~7.21 (m, 2H), 2-carboxamide 6.76 (s, 1H), 3.01 (s, 3H), 1.29 (s, 4H) 430 N-(3-chloro-5-(1-(3- LC/MS ESI (+): 671 (M + 1) isopropoxy-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.71 (s, 1H), (trifluoromethoxy)phenyl)cyclopropyl)phenyl)- 8.31 (brs, 1H), 8.21 (d, 1H, J = 7.4 Hz), 8.15 (d, 1H, 6-fluoro-5-(N- J = 10.5 Hz), 7.85 (m, 1H), 7.60 (s, 1H), 7.11 (s, 1H), methylmethylsulfonamido)benzo[b]thiophene- 6.78 (m, 2H), 6.73 (s, 1H), 4.63~4.66 (m, 1H), 2-carboxamide 3.30 (s, 3H), 3.14 (s, 3H), 1.32~1.34 (m, 4H), 1.25 (d, 6H, J = 6.0 Hz) 431 N-(3-chloro-5-(1-(3- LC/MS ESI (+): 639 (M + 1) isopropoxy-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), (trifluoromethoxy)phenyl)cyclopropyl)phenyl)- 9.87 (brs, 1H), 8.29 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 5- 7.85 (s, 1H), 7.80 (d, 1H, J = 2.0 Hz), 7.59 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.36 (dd, 1H, J = 8.7, 2.1 Hz), 7.09 (s, 1H), 6.76 (s, 1H), 2-carboxamide 6.75 (s, 1H), 6.72 (s, 1H), 4.62~4.68 (m, 1H), 3.02 (s, 3H), 1.32 (d, 4H, J = 9.5 Hz), 1.23 (d, 6H, J = 6.0 Hz) 432 N-(3-chloro-5-(1-(4- LC/MS ESI (+): 531 (M + 1) chlorophenyl)cyclopropyl)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 5- 9.89 (brs, 1H), 8.26 (s, 1H), 7.99 (d, 1H, J = 8.7 Hz), (methylsulfonamido)benzo[b]thiophene- 7.84 (s, 1H), 7.76 (s, 1H), 7.54 (s, 1H), 7.38 (d, 2H, 2-carboxamide J = 8.4 Hz), 7.33 (d, 1H, J = 8.7 Hz), 7.28 (d, 2H, J = 8.4 Hz), 7.02 (s, 1H), 2.98 (s, 3H), 1.31 (d, 4H, J = 6.2 Hz) 433 6-chloro-N-(3-chloro-5-(1-(4- LC/MS ESI (+): 565 (M + 1) chlorophenyl)cyclopropyl)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.66 (s, 1H), 5- 9.65 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 8.05 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.84 (t, 1H, J = 1.9 Hz), 7.53 (s, 1H), 7.39 (d, 2H, 2-carboxamide J = 8.5 Hz), 7.29 (d, 2H, J = 8.5 Hz), 7.04 (t, 1H, J = 1.6 Hz), 3.07 (s, 3H), 1.32 (d, 4H, J = 5.9 Hz)

Example 434 Synthesis of N-(3-benzoylphenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (30.0 mg, 0.12 mmol), 3-aminobenzophenone (26.0 mg, 0.13 mmol), and HATU (49.0 mg, 0.13 mmol) were dissolved in anhydrous DMF (2.0 mL), and DIPEA (42.0 μL, 0.24 mmol) was added. After stirring at 30° C. for 2 hours, the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:3) to obtain N-(3-benzoylphenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (20.0 mg, 38%) as a white solid.

LC/MS ESI (+): 434 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.76 (s, 1H), 10.42 (s, 1H), 9.64 (brs, 1H), 8.24 (s, 1H), 8.16 (d, 1H, J=8.0 Hz), 7.78 (d, 2H, J=6.9 Hz), 7.71 (t, 1H, J=7.3 Hz), 7.62 (m, 4H), 7.47 (d, 1H, J=7.6 Hz), 7.41 (dd, 2H, J=8.8, 1.9 Hz), 6.99 (dd, 1H, J=8.4, 1.9 Hz), 2.94 (s, 3H)

Example 435 Synthesis of N-(3-(1-hydroxy-1-phenylethyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of 1-(3-nitrophenyl)-1-phenylethanol

(3-Nitrophenyl)(phenyl)methanone (100.0 mg, 0.44 mmol) was dissolved in toluene (4.0 mL), and 1 M solution of Al(CH₃)₃ in n-heptane (1.8 mL, 1.76 mmol) and a catalytic amount of AcOH were added, followed by refluxing at 110° C. for 15 hours. The reaction mixture was cooled to room temperature and extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 1-(3-nitrophenyl)-1-phenylethanol (50.0 mg, 47%) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃): δ 8.35 (s, 1H), 8.09 (d, 1H, J=8.1 Hz), 7.73 (d, 1H, J=7.8 Hz), 7.28-7.49 (m, 6H), 2.29 (s, 1H), 2.00 (s, 3H)

(b) Synthesis of 1-(3-aminophenyl)-1-phenylethanol

1-(3-Nitrophenyl)-1-phenylethanol (50.0 mg, 0.21 mmol) was dissolved in a mixture of MeOH/H₂O (2.2 mL, 10/1 v/v), and Zn (54.0 mg, 0.82 mmol) and NH₄Cl (44.0 mg, 0.82 mmol) were added, and then ultrasonificated at 40° C. for 1 hour. The reaction mixture was filtered through Celite and extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=5:1) to obtain 1-(3-aminophenyl)-1-phenylethanol (17.0 mg, 38%) as a colorless oil.

LC/MS ESI (+): 214 (M+1)

(c) Synthesis of N-(3-(1-hydroxy-1-phenylethyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

6-(Methylsulfonamido)-1H-indole-2-carboxylic acid hydrochloride (22.0 mg, 0.09 mmol), 1-(3-aminophenyl)-1-phenylethanol (17.0 mg, 0.08 mmol), HATU (34.0 mg, 0.09 mmol), and DIPEA (21.0 μL, 0.17 mmol) were dissolved in anhydrous DMF (0.8 mL), followed by stirring at room temperature for 15 hours. The reaction mixture was extracted with CH₂Cl₂, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=9:1) to obtain N-(3-(1-hydroxy-1-phenylethyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (15.0 mg, 39%) as a white solid.

LC/MS ESI (+): 450 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.68 (s, 1H), 10.13 (s, 1H), 9.61 (s, 1H), 7.81 (s, 1H), 7.75 (d, 1H, J=8.0 Hz), 7.60 (d, 1H, J=8.8 Hz), 7.44 (d, 2H, J=8.0 Hz), 7.38 (s, 2H), 7.13-7.31 (m, 5H), 6.98 (dd, 1H J=8.4, 1.9 Hz), 5.75 (s, 1H), 2.93 (s, 3H), 1.84 (s, 3H)

Example 436 and Example 437 Synthesis of 6-(N-(2-amino-2-oxoethyl)methylsulfonamido)-N-(3-(2-(3-hydroxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-1H-indole-2-carboxamide and N-(3-(2-(3-(2-amino-2-oxoethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(N-(2-amino-2-oxoethyl)methylsulfonamido)-1H-indole-2-carboxamide (a) Synthesis of N-3-(2-(3-hydroxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide

To a solution of N-(3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (30.0 mg, 0.05 mmol) in anhydrous CH₂Cl₂ (1.0 mL), 1.0 M solution of BBr₃ in CH₂Cl₂ (160.0 μL, 0.16 mmol) was added at 0° C., followed by stirring at room temperature for 1 hour and 20 minutes. Water was added at 0° C. to quench the reaction, and the reaction mixture was extracted with CH₂Cl₂. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=9:1) to obtain N-(3-(2-(3-hydroxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (28.7 mg, 98%) as an off-white oil.

LC/MS ESI (+): 548 (M+1)

(b) Synthesis of 6-(N-(2-amino-2-oxoethyl)methylsulfonamido)-N-(3-(2-(3-hydroxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-1H-indole-2-carboxamide

N-(3-(2-(3-hydroxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide (48.0 mg, 0.09 mmol) was dissolved in anhydrous DMF (1.5 mL), and K₂CO₃ (18.2 mg, 0.13 mmol) and 2-iodoacetamide (19.5 mg, 0.11 mmol) were added. The reaction mixture was heated at 40° C. for 12 hours, water was added to quench the reaction, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (amine silica gel, CH₂Cl₂:MeOH=9:1) to obtain 6-(N-(2-amino-2-oxoethyl)methylsulfonamido)-N-(3-(2-(3-hydroxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-1H-indole-2-carboxamide (6.8 mg, 13%) as a white solid and N-(3-(2-(3-(2-amino-2-oxoethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(N-(2-amino-2-oxoethyl)methylsulfonamido)-1H-indole-2-carboxamide (2.1 mg, 4%) as a white solid.

Example 436

LC/MS ESI (+): 605 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.92 (s, 1H), 10.22 (s, 1H), 9.94 (s, 1H), 7.78 (d, 1H, J=8.0 Hz), 7.68 (d, 1H, J=8.8 Hz), 7.65 (s, 1H), 7.60 (s, 1H), 7.46 (s, 1H), 7.42 (s, 1H), 7.30 (t, 1H, J=8.0 Hz), 7.18-7.21 (m, 2H), 6.98 (d, 1H, J=7.6 Hz), 6.61 (s, 2H), 6.53 (s, 1H), 4.25 (s, 2H), 3.12 (s, 3H), 1.62 (s, 6H)

Example 437

LC/MS ESI (+): 662 (M+1)

¹H-NMR (300 MHz, DMSO-d₆): δ 11.93 (s, 1H), 10.22 (s, 1H), 7.78 (m, 1H), 7.66-7.69 (m, 2H), 7.63 (s, 1H), 7.59 (m, 1H), 7.42-7.46 (m, 3H), 7.30 (t, 1H, J=8.0 Hz), 7.17-7.21 (m, 2H), 6.97 (m, 1H), 6.91 (m, 1H), 6.78 (m, 1H), 6.73 (m, 1H), 4.44 (s, 2H), 4.24 (s, 2H), 3.12 (s, 3H), 1.65 (s, 6H)

Example 438 Synthesis of N-(3-chloro-5-((2,4-difluorophenyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of N-(3-chloro-5-nitrophenyl)-2,4-difluoroaniline

1-Bromo-3-chloro-5-nitrobenzene (100.0 mg, 0.42 mmol), 2,4-difluoroaniline (35.6 μL, 0.35 mmol), Pd₂(dba)₃CHCl₃ (18.3 mg, 0.02 mmol), BINAP (21.9 mg, 0.04 mmol) and NaOt-Bu (47.5 mg, 0.49 mmol) were added to anhydrous toluene (3.5 mL). The reaction was performed in a microwave with 150 W, at 110° C. for 30 minutes, and the reaction mixture was cooled to room temperature. Water was added, and the reaction mixture was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain N-(3-chloro-5-nitrophenyl)-2,4-difluoroaniline (76.6 mg, 76%) as a yellow solid.

LC/MS ESI (+): 285 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.68 (m, 1H), 7.58 (m, 1H), 7.31 (m, 1H), 7.11 (m, 1H), 6.91-7.00 (m, 2H), 5.79 (s, 1H)

(b) Synthesis of 5-chloro-N¹-(2,4-difluorophenyl)benzene-1,3-diamine

The synthesis procedure of Example 400-c was repeated except for using N-(3-chloro-5-nitrophenyl)-2,4-difluoroaniline (76.6 mg, 0.27 mmol) to obtain 5-chloro-N¹-(2,4-difluorophenyl)benzene-1,3-diamine (64.5 mg, 95%) as a red oil.

LC/MS ESI (+): 255 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.27 (m, 1H), 6.80-6.91 (m, 2H), 6.36 (m, 1H), 6.26 (m, 1H), 6.13 (m, 1H), 5.46 (s, 1H), 3.68 (s, 2H)

(c) Synthesis of N-(3-chloro-5-((2,4-difluorophenyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 5-chloro-N¹-(2,4-difluorophenyl)benzene-1,3-diamine (64.5 mg, 0.25 mmol) to obtain N-(3-chloro-5-((2,4-difluorophenyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (67.6 mg, 53%) as an off-white solid.

LC/MS ESI (+): 508 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.41 (s, 1H), 9.87 (brs, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 8.00 (d, 1H, J=8.8 Hz), 7.78 (d, 1H, J=2.0 Hz), 7.33-7.41 (m, 4H), 7.22 (s, 1H), 7.10 (m, 1H), 6.59 (m, 1H), 3.00 (s, 3H)

Example 439 Synthesis of N-(3-chloro-5-((2,4-difluorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

To a solution of N-(3-chloro-5-((2,4-difluorophenyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (Example 438) (22.3 mg, 0.04 mmol) in anhydrous CH₃CN (0.4 mL), 37 wt % formaldehyde aqueous solution (49.0 μL, 0.66 mmol), AcOH (3.8 μL, 0.07 mmol), and NaBH₃CN (5.5 mg, 0.09 mmol) were added. The reaction mixture was stirred at room temperature for 21 hours, water was added, and extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=1:1) to obtain N-(3-chloro-5-((2,4-difluorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (3.9 mg, 17%) as a white solid.

LC/MS ESI (+): 522 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.36 (s, 1H), 9.87 (brs, 1H), 8.23 (s, 1H), 7.98 (d, 1H, J=8.6 Hz), 7.76 (s, 1H), 7.41-7.52 (m, 3H), 7.33 (d, 1H, J=7.3 Hz), 7.22 (m, 1H), 6.93 (s, 1H), 6.46 (s, 1H), 3.22 (s, 3H), 2.98 (s, 3H)

Example 440 Synthesis of N-(3-chloro-5-((4-chlorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[L]thiophene-2-carboxamide (a) Synthesis of 3-chloro-N-(4-chlorophenyl)-5-nitroaniline

1-Bromo-3-chloro-5-nitrobenzene (200.0 mg, 0.85 mmol) and 4-chloroaniline (89.9 mg, 0.71 mmol) were dissolved in toluene (3.5 mL), and Pd₂(dba)₃CHCl₃ (36.5 mg, 0.04 mmol), BINAP (43.9 mg, 0.07 mmol) and NaOt-Bu (94.9 mg, 0.99 mmol) were added, followed by stirring in a microwave at 110° C. for 30 minutes. After cooling to room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 3-chloro-N-(4-chlorophenyl)-5-nitroaniline (107.1 mg, 54%) as an orange solid.

LC/MS ESI (+): 283 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.67 (s, 1H), 7.65 (s, 1H), 7.35 (d, 2H, J=8.6 Hz), 7.20 (s, 1H), 7.09 (d, 2H, J=8.6 Hz), 5.94 (s, 1H)

(b) Synthesis of 3-chloro-N-(4-chlorophenyl)-N-methyl-5-nitroaniline

3-Chloro-N-(4-chlorophenyl)-5-nitroaniline (70.7 mg, 0.25 mmol) was dissolved in anhydrous DMF (2.5 mL), and 60% NaH in mineral oil (15.0 mg, 0.38 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, and CH₃I (31.1 μL, 0.50 mmol) was added. After stirring at room temperature for 5 hours, the residue was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 3-chloro-N-(4-chlorophenyl)-N-methyl-5-nitroaniline (68.1 mg, 92%) as a yellow solid.

LC/MS ESI (+): 297 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.59 (m, 1H), 7.47 (m, 1H), 7.40 (d, 2H, J=8.7 Hz), 7.13 (d, 2H, J=8.7 Hz), 6.97 (m, 1H), 3.34 (s, 3H)

(c) Synthesis of 5-chloro-N¹-(4-chlorophenyl)-N¹-methylbenzene-1,3-diamine

The synthesis procedure of Intermediate 40 was repeated except for using 3-chloro-N-(4-chlorophenyl)-N-methyl-5-nitroaniline (73.3 mg, 0.25 mmol) to obtain 5-chloro-N¹-(4-chlorophenyl)-N¹-methylbenzene-1,3-diamine (59.1 mg, 90%) as a brown liquid.

LC/MS ESI (+): 267 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.26 (d, 2H, J=8.9 Hz), 7.00 (d, 2H, J=8.9 Hz), 6.31 (m, 1H), 6.25 (m, 1H), 6.08 (m, 1H), 3.64 (s, 2H), 3.23 (s, 3H)

(d) Synthesis of N-(3-chloro-5-((4-chlorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 5-chloro-N¹-(4-chlorophenyl)-N¹-methylbenzene-1,3-diamine (29.5 mg, 0.11 mmol) to obtain N-(3-chloro-5-((4-chlorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (19.7 mg, 35%).

LC/MS ESI (+): 520 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.44 (s, 1H), 9.87 (brs, 1H), 8.26 (s, 1H), 8.01 (d, 1H, J=8.7 Hz), 7.79 (d, 1H, J=1.9 Hz), 7.52 (m, 1H), 7.42 (d, 2H, J=8.8 Hz), 7.35 (dd, 1H, J=8.7, 2.1 Hz), 7.24 (m, 1H), 7.19 (d, 2H, J=8.8 Hz), 6.72 (m, 1H), 3.27 (s, 3H), 3.01 (s, 3H)

Through the synthetic method according to Example 440, compounds of Example 441 and Example 442 were synthesized, and the data of each example are as follows.

TABLE 33 Ex. Compound Analysis data 441 6-chloro-N-(3-chloro-5-((4- LC/MS ESI (+): 554 (M + 1) chlorophenyl)(methyl)amino)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 5- 9.62 (s, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.03 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.51 (s, 1H), 7.42 (d, 2H, J = 8.7 Hz), 7.18~7.22 (m, 3H), 2-carboxamide 6.73 (s, 1H), 3.27 (s, 3H), 3.06 (s, 3H) 442 6-chloro-N-(3-chloro-5-((2,4- LC/MS ESI (+): 556 (M + 1) difluorophenyl)(methyl)amino)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.46 (s, 1H), 5- 9.61 (s, 1H), 8.33 (s, 1H), 8.25 (s, 1H), 8.02 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.41~7.52 (m, 3H), 7.21 (m, 1H), 6.90 (s, 1H), 2-carboxamide 6.48 (s, 1H), 3.22 (s, 3H), 3.05 (s, 3H)

Example 443 Synthesis of N-(3-chloro-5-((3-isopropoxy-5-(trifluoromethoxy)phenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 3-isopropoxy-N-methyl-5-(trifluoromethoxy)aniline

1-Bromo-3-isopropoxy-5-(trifluoromethoxy)benzene (300.0 mg, 1.00 mmol) and 2.0 M solution of methylamine in THF (7.5 mL, 15.0 mmol) were added to toluene (5.0 mL), and Pd₂(dba)₃.CHCl₃ (51.9 mg, 0.05 mmol), BINAP (93.7 mg, 0.15 mmol) and Cs₂CO₃ (490.2 mg, 1.51 mmol) were added, followed by stirring at 100° C. for 16 hours. After cooling to room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 3-isopropoxy-N-methyl-5-(trifluoromethoxy)aniline (120.9 mg, 48%) as a yellow solid.

LC/MS ESI (+): 250 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 6.11 (s, 1H), 6.03-6.04 (m, 2H), 4.48 (m, 1H), 3.82 (s, 1H), 2.81 (d, 3H, J=4.3 Hz), 1.32 (d, 6H, J=6.0 Hz)

(b) Synthesis of 3-chloro-N-(3-isopropoxy-5-(trifluoromethoxy)phenyl)-N-methyl-5-nitroaniline

3-Isopropoxy-N-methyl-5-(trifluoromethoxy)aniline (120.9 mg, 0.49 mmol) and 1-bromo-3-chloro-5-nitrobenzene (137.6 mg, 0.58 mmol) were added to toluene (2.4 mL), and Pd₂(dba)₃CHCl₃ (25.1 mg, 0.02 mmol), BINAP (30.2 mg, 0.05 mmol) and NaOt-Bu (65.3 mg, 0.68 mmol) were added, followed by stirring at 110° C. for 40 minutes by using a microwave. The reaction mixture was cooled to room temperature, extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 3-chloro-N-(3-isopropoxy-5-(trifluoromethoxy)phenyl)-N-methyl-5-nitroaniline (151.3 mg, 77%) as a yellow liquid.

LC/MS ESI (+): 405 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.66 (s, 1H), 7.59 (s, 1H), 7.11 (s, 1H), 6.55-6.60 (m, 3H), 4.50 (m, 1H), 3.35 (s, 3H), 1.35 (d, 6H, J=6.0 Hz)

(c) Synthesis of 5-chloro-N¹-(3-isopropoxy-5-(trifluoromethoxy)phenyl)-N¹-methylbenzene-1,3-diamine

The synthesis procedure of Intermediate 40 was repeated except for using 3-chloro-N-(3-isopropoxy-5-(trifluoromethoxy)phenyl)-N-methyl-5-nitroaniline (151.3 mg, 0.37 mmol) to obtain 5-chloro-N¹-(3-isopropoxy-5-(trifluoromethoxy)phenyl)-N¹-methylbenzene-1,3-diamine (123.7 mg, 88%) as a brown liquid.

LC/MS ESI (+): 375 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 6.45 (s, 1H), 6.37-6.40 (m, 2H), 6.36 (s, 1H), 6.33 (s, 1H), 6.24 (s, 1H), 4.46 (m, 1H), 3.69 (s, 2H), 3.29 (s, 3H), 1.31 (d, 6H, J=6.0 Hz)

(d) Synthesis of N-(3-chloro-5-((3-isopropoxy-5-(trifluoromethoxy)phenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 5-chloro-N¹-(3-isopropoxy-5-(trifluoromethoxy)phenyl)-N¹-methylbenz ene-1,3-diamine (40.0 mg, 0.11 mmol) to obtain N-(3-chloro-5-((3-isopropoxy-5-(trifluoromethoxy)phenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (25.4 mg, 38%).

LC/MS ESI (+): 628 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.51 (s, 1H), 9.87 (brs, 1H), 8.27 (s, 1H), 8.01 (d, 1H, J=8.7 Hz), 7.79 (m, 1H), 7.64 (s, 1H), 7.44 (s, 1H), 7.36 (dd, 1H, J=8.8, 1.7 Hz), 6.90 (s, 1H), 6.52-6.55 (m, 3H), 4.61 (m, 1H), 3.29 (s, 3H), 3.01 (s, 3H), 1.25 (d, 6H, J=6.0 Hz)

Example 444 Synthesis of N-(3-chloro-5-(2,4-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 1-(3-chloro-5-nitrophenoxy)-2,4-difluorobenzene

1-Bromo-3-chloro-5-nitrobenzene (100.0 mg, 0.42 mmol), 2,4-difluorophenol (40.4 μL, 0.42 mmol), CuI (40.3 mg, 0.21 mmol), N,N-dimethylglycine (43.6 mg, 0.42 mmol) and Cs₂CO₃ (413.5 mg, 1.27 mmol) were added to anhydrous 1,4-dioxane (2.1 mL). The reaction was performed in a microwave with 100 W, at 90° C. for 1 hour, and the reaction mixture was cooled to room temperature. Water was added, followed by extracting with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 1-(3-chloro-5-nitrophenoxy)-2,4-difluorobenzene (31.1 mg, 26%) as a yellow oil.

¹H-NMR (400 MHz, CDCl₃): δ 7.93 (m, 1H), 7.61 (m, 1H), 7.24 (m, 1H), 7.18 (m, 1H), 6.94-7.05 (m, 2H)

(b) Synthesis of 3-chloro-5-(2,4-difluorophenoxy)aniline

The synthesis procedure of Intermediate 40 was repeated except for using 1-(3-chloro-5-nitrophenoxy)-2,4-difluorobenzene (31.1 mg, 0.11 mmol) to obtain 3-chloro-5-(2,4-difluorophenoxy)aniline (22.3 mg, 80%) as a yellowish brown oil.

LC/MS ESI (+): 256 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 7.09 (m, 1H), 6.95 (m, 1H), 6.87 (m, 1H), 6.39 (m, 1H), 6.27 (m, 1H), 6.13 (m, 1H), 3.76 (s, 2H)

(c) Synthesis of N-(3-chloro-5-(2,4-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-chloro-5-(2,4-difluorophenoxy)aniline (22.3 mg, 0.08 mmol) to obtain N-(3-chloro-5-(2,4-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (11.5 mg, 27%) as a white solid.

LC/MS ESI (+): 509 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.87 (brs, 1H), 8.24 (s, 1H), 7.99 (d, 1H, J=8.7 Hz), 7.77 (s, 1H), 7.73 (s, 1H), 7.56 (m, 1H), 7.45 (m, 1H), 7.34 (d, 1H, J=8.7 Hz), 7.30 (s, 1H), 7.21 (m, 1H), 6.89 (s, 1H), 2.98 (s, 3H)

Through the synthetic method according to Example 444, compounds from Example 445 to Example 485 were synthesized, and the data of each example are as follows.

TABLE 34 Ex. Compound Analysis data 445 N-(3-chloro-5-(4- LC/MS ESI (+): 507 (M + 1) chlorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.54 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.80 (s, 1H), 8.20 (s, 1H), 7.95 (d, 1H, J = 8.7 Hz), 7.73 (s, 2-carboxamide 1H), 7.69 (s, 1H), 7.44 (d, 2H, J = 8.9 Hz), 7.28~7.31 (m, 2H), 7.11 (d, 2H, J = 8.9 Hz), 6.85 (s, 1H), 2.95 (s, 3H) 446 N-(3-chloro-5-(4- LC/MS ESI (+): 491 (M + 1) fluorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): (methylsulfonamido)benzo[b]thiophene- δ 10.58 (s, 1H), 9.87 (brs, 1H), 8.26 (s, 1H), 8.01 (d, 2-carboxamide 1H, J = 8.8 Hz), 7.79 (m, 1H), 7.72 (s, 1H), 7.36 (dd, 1H, J = 8.7, 2.0 Hz), 7.28~7.33 (m, 3H), 7.19~7.22 (m, 2H), 6.86 (m, 1H), 3.01 (s, 3H) 447 N-(3-chloro-5-(4- LC/MS ESI (+): 503 (M + 1) methoxyphenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.86 (brs, 1H), 8.26 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.78 (d, 2-carboxamide 1H, J = 1.9 Hz), 7.69 (m, 1H), 7.35 (dd, 1H, J = 8.7, 2.1 Hz), 7.27 (m, 1H), 7.11 (d, 2H, J = 9.1 Hz), 7.02 (d, 2H, J = 9.1 Hz), 6.78 (m, 1H), 3.78 (s, 3H), 3.00 (s, 3H) 448 N-(3-chloro-5-(2,5- LC/MS ESI (+): 509 (M + 1) difluorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.61 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.86 (brs, 1H), 8.26 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.79 (d, 2-carboxamide 1H, J = 1.9 Hz), 7.76 (m, 1H), 7.53 (m, 1H), 7.32~7.37 (m, 3H), 7.20 (m, 1H), 6.96 (m, 1H), 3.00 (s, 3H) 449 6-chloro-N-(3-chloro-5-(4- LC/MS ESI (+): 541 (M + 1) chlorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.69 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.63 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 2-carboxamide 7.75 (s, 1H), 7.51 (d, 2H, J = 8.8 Hz), 7.34 (s, 1H), 7.17 (d, 2H, J = 8.8 Hz), 6.92 (s, 1H), 3.03 (s, 3H) 450 N-(3-chloro-5-(3- LC/MS ESI (+): 557 (M + 1) (trifluoromethoxy)phenoxy)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.65 (s, 1H), 5- 9.88 (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 7.80 (s, (methylsulfonamido)benzo[b]thiophene- 2H), 7.60 (t, 1H, J = 8.0 Hz), 7.45 (s, 1H), 7.37 (d, 1H, 2-carboxamide J = 8.8 Hz), 7.25 (d, 1H, J = 8.8 Hz), 7.20 (s, 1H), 7.17 (d, 1H, J = 8.4 Hz), 6.99 (s, 1H), 3.01 (s, 3H) 451 N-(3-chloro-5-(4- LC/MS ESI (+): 498 (M + 1) cyanophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.60 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.80 (brs, 1H), 8.21 (s, 1H), 7.95 (d, 1H, J = 8.8 Hz), 7.85 (d, 2-carboxamide 2H, J = 8.8 Hz), 7.74 (d, 2H, J = 5.6 Hz), 7.43 (s, 1H), 7.29 (d, 1H, J = 8.8 Hz), 7.19 (d, 2H, J = 8.4 Hz), 7.00 (s, 1H), 2.94 (s, 3H) 452 N-(3-chloro-5-(3-isopropoxy- LC/MS ESI (+): 615 (M + 1) 5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 1H), (trifluoromethoxy)phenoxy)phenyl)- 9.87 (brs, 1H), 8.27 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), 5- 7.79~7.80 (m, 2H), 7.43 (s, 1H), 7.36 (dd, 1H, J = 8.7, (methylsulfonamido)benzo[b]thiophene- 1.9 Hz), 6.97 (s, 1H), 6.76 (s, 1H), 6.69 (m, 1H), 2-carboxamide 6.66 (s, 1H), 4.68 (m, 1H). 3.01 (s, 3H), 1.26 (d, 6H, J = 6.0 Hz) 453 6-bromo-N-(3-chloro-5-(4- LC/MS ESI (+): 585 (M + 1) chlorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.49 (s, 1H), 8.42 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 2-carboxamide 7.68 (s, 1H), 7.44 (d, 2H, J = 8.8 Hz), 7.28 (s, 1H), 7.11 (d, 2H, J = 8.8 Hz), 6.86 (s, 1H), 2.99 (s, 3H) 454 N-(3-chloro-5-(4- LC/MS ESI (+): 557 (M + 1) (trifluoromethoxy)phenoxy)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.62 (s, 1H), 5- 9.93 (brs, 1H), 8.26 (s, 1H), 7.99 (d, 1H, J = 8.8 Hz), (methylsulfonamido)benzo[b]thiophene- 7.77~7.80 (m, 2H), 7.47 (d, 2H, J = 8.8 Hz), 7.41 (s, 2-carboxamide 1H), 7.35 (d, 1H, J = 8.4 Hz), 7.26 (d, 2H, J = 8.8 Hz), 6.96 (s, 1H), 2.99 (s, 3H) 455 N-(3-chloro-5-(3- LC/MS ESI (+): 541 (M + 1) (trifluoromethyl)phenoxy)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 1H), 5- 9.86 (brs, 1H), 8.27 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), (methylsulfonamido)benzo[b]thiophene- 7.79 (m, 1H), 7.78 (m, 1H), 7.69 (t, 1H, J = 7.9 Hz), 7.59 (d, 2-carboxamide 1H, J = 7.8 Hz), 7.49 (s, 1H), 7.40~7.44 (m, 2H), 7.36 (dd, 1H, J = 8.7, 2.0 Hz), 6.98 (s, 1H), 3.01 (s, 3H) 456 N-(3-chloro-5-(3- LC/MS ESI (+): 507 (M + 1) chlorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.93 (brs, 1H), 8.27 (s, 1H), 8.01 (d, 1H, J = 8.0 Hz), 7.79 (s, 2-carboxamide 2H), 7.49 (t, 1H, J = 8.0 Hz), 7.40 (s, 1H), 7.31~7.37 (m, 2H), 7.26 (s, 1H), 7.13 (dd, 1H, J = 8.0, 4.0 Hz), 6.97 (s, 1H), 3.00 (s, 3H) 457 N-(3-chloro-5-(3- LC/MS ESI (+): 503 (M + 1) methoxyphenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.61 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.88 (brs, 1H), 8.29 (s, 1H), 8.03 (d, 1H, J = 8.4 Hz), 7.80 (s, 2-carboxamide 1H), 7.75 (s, 1H), 7.35~7.39 (m, 3H), 6.89 (s, 1H), 6.83 (dd, 1H, J = 8.0, 2.0 Hz), 6.73 (s, 1H), 6.69 (dd, 1H, J = 8.0, 2.0 Hz), 3.78 (s, 3H), 3.02 (s, 3H) 458 N-(3-chloro-5-(3-chloro-5- LC/MS ESI (+): 532 (M + 1) cyanophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.67 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.89 (brs, 1H), 8.29 (s, 1H), 8.04 (d, 1H, J = 8.8 Hz), 7.92 (s, 2-carboxamide 1H), 7.82~7.83 (m, 2H), 7.71 (s, 1H), 7.66 (t, 1H, J = 2.0 Hz), 7.44 (s, 1H), 7.37 (dd, 1H, J = 8.8, 2.0 Hz), 7.06 (s, 1H), 3.03 (s, 3H) 459 N-(3-chloro-5-(3- LC/MS ESI (+): 498 (M + 1) cyanophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.65 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.88 (brs, 1H), 8.29 (s, 1H), 8.04 (d, 1H, J = 8.8 Hz), 2-carboxamide 7.80~7.81 (m, 2H), 7.65~7.73 (m, 3H), 7.49~7.52 (m, 1H), 7.41 (t, 1H, J = 2.0 Hz), 7.38 (dd, 1H, J = 8.8, 2.0 Hz), 7.00 (s, 1H), 3.03 (s, 3H) 460 N-(3-chloro-5-(3,4- LC/MS ESI (+): 509 (M + 1) difluorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.60 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.89 (brs, 1H), 8.27 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.79 (d, 2-carboxamide 1H, J = 2.0 Hz), 7.76 (m, 1H), 7.54 (m, 1H), 7.34~7.42 (m, 3H), 7.02 (m, 1H), 6.92 (m, 1H), 3.00 (s, 3H) 461 N-(3-chloro-5-(3-chloro-4- LC/MS ESI (+): 525 (M + 1) fluorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.60 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.89 (brs, 1H), 8.26 (s, 1H), 8.01 (d, 1H, J = 8.7 Hz), 7.79 (d, 2-carboxamide 1H, J = 2.0 Hz), 7.76 (m, 1H), 7.48~7.54 (m, 2H), 7.33~7.37 (m, 2H), 7.20 (m, 1H), 6.93 (m, 1H), 3.00 (s, 3H) 462 N-(3-chloro-5-(2,4- LC/MS ESI (+): 541 (M + 1) dichlorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.58 (s, 1 H), (methylsulfonamido)benzo[b]thiophene- 9.90 (brs, 1H), 8.25 (s, 1H), 8.00 (d, 1H, J = 8.7 Hz), 7.86 (d, 2-carboxamide 1H, J = 2.5 Hz), 7.76~7.78 (m, 2H), 7.53 (dd, 1H, J = 8.7, 2.5 Hz), 7.33~7.36 (m, 2H), 7.25 (m, 1H), 6.92 (m, 1H), 2.99 (s, 3H) 463 N-(3-chloro-5-(3,5- LC/MS ESI (+): 509 (M + 1) difluorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.89 (brs, 1H), 8.28 (s, 1H), 8.01 (d, 1H, J = 8.8 Hz), 2-carboxamide 7.79~7.81 (m, 2H), 7.45 (m, 1H), 7.35 (dd, 1H, J = 8.7, 2.1 Hz), 7.11 (tt, 1H, J = 9.4, 2.3 Hz), 7.02 (m, 1H), 6.90~6.97 (m, 2H), 3.00 (s, 3H) 464 N-(3-chloro-5-(3,5- LC/MS ESI (+): 541 (M + 1) dichlorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.65 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.89 (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 2-carboxamide 7.80~7.82 (m, 2H), 7.48 (m, 1H), 7.41 (m, 1H), 7.36 (dd, 1H, J = 8.7, 2.1 Hz), 7.26 (d, 2H, J = 1.8 Hz), 7.03 (m, 1H), 3.01 (s, 3H) 465 N-(3-chloro-5-(4- LC/MS ESI (+): 541 (M + 1) (trifluoromethyl)phenoxy)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.64 (s, 1H), 5- 9.89 (brs, 1H), 8.27 (s, 1H), 8.01 (d, 1H, J = 8.8 Hz), (methylsulfonamido)benzo[b]thiophene- 7.79~7.82 (m, 4H), 7.46 (s, 1H), 7.35 (dd, 1H, J = 8.7, 2-carboxamide 2.0 Hz), 7.29 (d, 2H, J = 8.6 Hz), 7.05 (s, 1H), 3.00 (s, 3H) 466 N-(3-chloro-5-(4-chloro-3- LC/MS ESI (+): 525 (M + 1) fluorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.89 (brs, 1H), 8.27 (s, 1H), 8.02 (d, 1H, J = 8.8 Hz), 2-carboxamide 7.78~7.80 (m, 2H), 7.66 (t, 1H, J = 8.7 Hz), 7.40 (m, 1H), 7.33~7.37 (m, 2H), 7.02 (m, 1H), 6.99 (m, 1H), 3.01 (s, 3H) 467 N-(3-chloro-5-(3-chloro-5- LC/MS ESI (+): 591 (M + 1) (trifluoromethoxy)phenoxy)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.66 (s, 1H), 5- 9.89 (brs, 1H), 8.28 (s, 1H), 8.02 (d, 1H, J = 8.7 Hz), (methylsulfonamido)benzo[b]thiophene- 7.80~7.82 (m, 2H), 7.46 (m, 1H), 7.42 (m, 1H), 2-carboxamide 7.36 (dd, 1H, J = 8.7, 2.1 Hz), 7.30 (m, 1H), 7.21 (m, 1H), 7.05 (m, 1H), 3.01 (s, 3H) 468 N-(3-chloro-5-(4-chloro-3- LC/MS ESI (+): 591 (M + 1) (trifluoromethoxy)phenoxy)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 5- 9.88 (brs, 1H), 8.20 (s, 1H), 7.94 (d, 1H, J = 8.7 Hz), (methylsulfonamido)benzo[b]thiophene- 7.72~7.73 (m, 2H), 7.69 (d, 1H, J = 8.9 Hz), 2-carboxamide 7.36~7.37 (m, 2H), 7.28 (dd, 1H, J = 8.7, 2.1 Hz), 7.14 (dd, 1H, J = 8.9, 2.8 Hz), 6.95 (s, 1H), 2.93 (s, 3H) 469 N-(3-chloro-5-(3-chloro-5- LC/MS ESI (+): 525 (M + 1) fluorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.66 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.90 (brs, 1H), 8.29 (s, 1H), 8.02 (m, 1H), 7.82 (s, 1H), 2-carboxamide 7.80 (m, 1H), 7.44 (s, 1H), 7.31~7.38 (m, 2H), 7.09~7.12 (m, 2H), 7.04 (s, 1H), 3.01 (s, 3H) 470 N-(3-chloro-5-(4-fluoro-3- LC/MS ESI (+): 575 (M + 1) (trifluoromethoxy)phenoxy)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H), 5- 9.89 (brs, 1H), 8.28 (s, 1H), 8.03 (d, 1H, J = 9.2 Hz), 7.81 (s, (methylsulfonamido)benzo[b]thiophene- 1H), 7.78 (s, 1H), 7.63 (t, 1H, J = 9.2 Hz), 7.51 (m, 1H), 2-carboxamide 7.40 (s, 1H), 7.37 (dd, 1H, J = 8.8, 2.0 Hz), 7.27 (m, 1H), 6.96 (s, 1H), 3.02 (s, 3H) 471 6-chloro-N-(3-chloro-5- LC/MS ESI (+): 514 (M + 1) (thiazol-2-yloxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.67 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 7.98 (s, 1H), 2-carboxamide 7.78 (s, 1H), 7.67 (s, 1H), 7.28~7.31 (m, 2H), 7.21 (s, 1H), 2.98 (s, 3H) 472 6-chloro-N-(3-chloro-5- LC/MS ESI (+): 514 (M + 1) (thiazol-5-yloxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.58 (s, 1H), 8.81 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 2-carboxamide 7.97 (s, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.45 (s, 1H), 6.99 (s, 1H), 2.98 (s, 3H) 473 6-chloro-N-(3-chloro-5-((5- LC/MS ESI (+): 547 (M + 1) chlorothiophen-2- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 1H), yl)oxy)phenyl)-5- 9.67 (brs, 1H), 8.32 (s, 1H), 8.28 (s, 1H), 8.02 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.79 (s, 1H), 7.54 (s, 1H), 7.04 (d, 1H, J = 4.1 Hz), 7.03 (s, 2-carboxamide 1H), 6.77 (d, 1H, J = 4.1 Hz), 3.03 (s, 3H) 474 6-chloro-N-(3-chloro-5-(3- LC/MS ESI (+): 571 (M + 1) chloro-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 1H), methoxyphenoxy)phenyl)-5- 9.63 (brs, 1H), 8.36 (s, 1H), 8.29 (s, 1H), 8.05 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.78 (m, 1H), 7.37 (m, 1H), 6.96 (m, 1H), 6.92 (m, 1H), 2-carboxamide 6.77 (m, 1H), 6.71 (m, 1H), 3.79 (s, 3H), 3.06 (s, 3H) 475 6-chloro-N-(3-chloro-5-(3- LC/MS ESI (+): 557 (M + 1) chloro-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.66 (s, 1H), hydroxyphenoxy)phenyl)-5- 10.24 (s, 1H), 8.20~8.24 (m, 2H), 7.95 (s, 1H), 7.78 (m, (methylsulfonamido)benzo[b]thiophene- 1H), 7.37 (m, 1H), 6.96 (m, 1H), 6.66 (m, 1H), 2-carboxamide 6.63 (m, 1H), 6.43 (m, 1H), 2.94 (s, 3H) 476 6-chloro-N-(3-chloro-5-(3- LC/MS ESI (+): 559 (M + 1) chloro-4- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 1H), fluorophenoxy)phenyl)-5- 9.64 (s, 1H), 8.34 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.76 (m, 1H), 7.49~7.54 (m, 2H), 7.32 (m, 1H), 7.20 (m, 2-carboxamide 1H), 6.94 (m, 1H), 3.05 (s, 3H) 477 6-chloro-N-(3-chloro-5-(4- LC/MS ESI (+): 559 (M + 1) chloro-3- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 1H), fluorophenoxy)phenyl)-5- 9.65 (s, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.78 (m, 1H), 7.66 (t, 1H, J = 8.7 Hz), 7.39 (m, 1H), 2-carboxamide 7.35 (dd, 1H, J = 10.4, 2.7 Hz), 7.00~7.04 (m, 2H), 3.05 (s, 3H) 478 6-chloro-N-(3-chloro-5-(4- LC/MS ESI (+): 525 (M + 1) fluorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.62 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.57 (brs, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 7.97 (s, 1H), 2-carboxamide 7.66 (s, 1H), 7.22~7.26 (m, 3H), 7.12~7.16 (m, 2H), 6.80 (s, 1H), 2.98 (s, 3H) 479 6-chloro-N-(3-chloro-5-(3- LC/MS ESI (+): 591 (M + 1) (trifluoromethoxy)phenoxy)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.68 (s, 1H), 5- 9.58 (brs, 1H), 8.28 (s, 1H), 8.21 (s, 1H), 7.97 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.72 (s, 1H), 7.50 (t, 1H, J = 8.0 Hz), 7.35 (s, 1H), 2-carboxamide 7.08~7.18 (m, 3H), 6.92 (s, 1H), 2.98 (s, 3H) 480 6-chloro-N-(3-chloro-5-(4- LC/MS ESI (+): 591 (M + 1) (trifluoromethoxy)phenoxy)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 1H), 5- 9.69 (brs, 1H), 8.32 (s, 1H), 8.27 (s, 1H), 8.02 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.78 (s, 1H), 7.46 (d, 2H, J = 8.7 Hz), 7.37 (s, 1H), 7.25 (d, 2 2-carboxamide H, J = 9.0 Hz), 6.96 (s, 1H), 3.03 (s, 3H) 481 6-chloro-N-(3-chloro-5-(3,4- LC/MS ESI (+): 543 (M + 1) difluorophenoxy)phenyl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.63 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.60 (brs, 1H), 8.25 (s, 1H), 8.20 (s, 1H), 7.95 (s, 1H), 2-carboxamide 7.69 (s, 1H), 7.48 (m, 1H), 7.35 (m, 1H), 7.28 (m, 1H), 6.96 (m, 1H), 6.87 (t, 1H, J = 1.9 Hz), 2.96 (s, 3H) 482 6-chloro-N-(3-chloro-5-(4- LC/MS ESI (+): 575 (M + 1) (trifluoromethyl)phenoxy)phenyl)- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 1H), 5- 9.67 (s, 1H), 8.35 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.80~7.82 (m, 3H), 7.44 (s, 1H), 7.30 (d, 2H, 2-carboxamide J = 8.3 Hz), 7.07 (s, 1H), 3.05 (s, 3H) 483 6-chloro-N-(3-chloro-5-(3- LC/MS ESI (+): 559 (M + 1) chloro-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.74 (s, 1H), fluorophenoxy)phenyl)-5- 9.63 (brs, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 8.03 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.80 (m, 1H), 7.42 (m, 1H), 7.31 (dt, 1H, J = 8.6, 2.0 Hz), 2-carboxamide 7.07~7.11 (m, 2H), 7.03 (m, 1H), 3.04 (s, 3H) 484 6-chloro-N-(3-chloro-5-(3- LC/MS ESI (+): 555 (M + 1) fluoro-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.67 (s, 1H), methoxyphenoxy)phenyl)-5- 9.66 (brs, 1H), 8.24~8.26 (m, 2H), 7.98 (m, 1H), 7.77 (m, (methylsulfonamido)benzo[b]thiophene- 1H), 7.39 (m, 1H), 6.95 (m, 1H), 6.72 (dt, 1H, J = 10.9, 2-carboxamide 2.2 Hz), 6.56~6.60 (m, 2H), 3.78 (s, 3H), 2.98 (s, 3H) 485 5-chloro-N-(3-chloro-5-(4- LC/MS ESI (+): 541 (M + 1) chlorophenoxy)phenyl)-6- ¹H-NMR (400 MHz, DMSO-d₆): δ 10.73 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.68 (s, 1H), 8.22~8.23 (m, 2H), 8.14 (s, 1H), 7.75 (m, 1H), 2-carboxamide 7.51 (d, 2H, J = 8.9 Hz), 7.35 (m, 1H), 7.18 (d, 2H, J = 8.9 Hz), 6.93 (m, 1H), 3.11 (s, 3H)

Example 486 Synthesis of 6-chloro-N-(3-chloro-5-(cyclohexyloxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 1-chloro-3-(cyclohexyloxy)-5-nitrobenzene

3-Chloro-5-nitrophenol (50.0 mg, 0.29 mmol) was dissolved in anhydrous THF (2.9 mL), and cyclohexanol (58.0 mg, 0.58 mmol), 2.2 M solution of DEAD in toluene (0.3 mL, 0.58 mmol) and PPh₃ (152.0 mg, 0.58 mmol) were added at 0° C. The reaction mixture was stirred at room temperature for 15 hours, and the residue was extracted with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 1-chloro-3-(cyclohexyloxy)-5-nitrobenzene (45.0 mg, 61%) as a colorless liquid.

¹H-NMR (400 MHz, CDCl₃): δ 7.76 (s, 1H), 7.62 (s, 1H), 7.19 (s, 1H), 4.33 (m, 1H), 1.95-1.99 (m, 2H), 1.79-1.82 (m, 2H), 1.55-1.61 (m, 2H), 1.37-1.47 (m, 4H)

(b) Synthesis of 3-chloro-5-(cyclohexyloxy)aniline

The synthesis procedure of Intermediate 40 was repeated except for using 1-chloro-3-(cyclohexyloxy)-5-nitrobenzene (45.0 mg, 0.18 mmol) to obtain 3-chloro-5-(cyclohexyloxy)aniline (22.0 mg, 55%) as a colorless liquid.

LC/MS ESI (+): 226 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 6.31 (s, 1H), 6.26 (s, 1H), 6.10 (s, 1H), 4.15 (m, 1H), 3.67 (brs, 2H), 1.93-1.97 (m, 2H), 1.76-1.79 (m, 2H), 1.44-1.53 (m, 2H), 1.25-1.39 (m, 4H)

(c) Synthesis of 6-chloro-N-(3-chloro-5-(cyclohexyloxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-chloro-5-(cyclohexyloxy)aniline (33.0 mg, 0.11 mmol) to obtain 6-chloro-N-(3-chloro-5-(cyclohexyloxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (8.0 mg, 18%).

LC/MS ESI (+): 513 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.52 (s, 1H), 9.59 (brs, 1H), 8.25 (s, 1H), 8.22 (s, 1H), 7.96 (s, 1H), 7.41 (s, 1H), 7.28 (s, 1H), 6.73 (s, 1H), 4.28 (m, 1H), 2.96 (s, 3H), 1.84-1.89 (m, 2H), 1.63-1.68 (m, 2H), 1.21-1.49 (m, 6H)

Example 487 Synthesis of 6-chloro-N-(3-chloro-5-((5-methylthiophen-2-yl)oxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 5-(3-chloro-5-nitrophenoxy)thiophene-2-carbaldehyde

3-Chloro-5-nitrophenol (200.0 mg, 1.15 mmol) and 5-bromothiophene-2-carbaldehyde (136.0 μL, 0.32 mmol) were dissolved in DMSO (4.0 mL), and K₂CO₃ (318.4 mg, 2.30 mmol) was added, followed by stirring in a microwave at 90° C. for 3 hours. After cooling to room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=5:1) to obtain 5-(3-chloro-5-nitrophenoxy)thiophene-2-carbaldehyde (130.0 mg, 40%) as a colorless liquid.

LC/MS ESI (+): 284 (M+1)

¹H-NMR (400 MHz, CDCl₃): 8, 9.81 (s, 1H), 8.07 (s, 1H), 7.90 (s, 1H), 7.62 (d, 1H, J=4.0 Hz), 7.49 (s, 1H), 6.71 (d, 1H, J=4.0 Hz)

(b) Synthesis of 3-chloro-5-((5-methylthiophen-2-yl)oxy)aniline

5-(3-Chloro-5-nitrophenoxy)thiophene-2-carbaldehyde (88.0 mg, 0.31 mmol) and hydrazine monohydrate (35.7 μL, 0.93 mmol) were dissolved in diethylene glycol (0.1 mL), followed by stirring at 180° C. for 1 hour. After cooling to 100° C., KOH (52.1 mg, 0.93 mmol) was added to the reaction mixture, followed by stirring at 120° C. for another 2 hours. After cooling to room temperature, the reaction mixture was extracted with Et₂O, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=4:1) to obtain 3-chloro-5-((5-methylthiophen-2-yl)oxy)aniline (40.0 mg, 54%) as a yellow liquid.

LC/MS ESI (+): 240 (M+1)

¹H-NMR (400 MHz, CDCl₃): 8, 6.44-6.46 (m, 2H), 6.38 (s, 1H), 6.36 (d, 1H, J=3.6 Hz), 6.25 (s, 1H), 3.76 (brs, 2H), 2.41 (s, 3H)

(c) Synthesis of 6-chloro-N-(3-chloro-5-((5-methylthiophen-2-yl)oxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-chloro-5-((5-methylthiophen-2-yl)oxy)aniline (35.0 mg, 0.15 mmol) to obtain 6-chloro-N-(3-chloro-5-((5-methylthiophen-2-yl)oxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (4.0 mg, 5%).

LC/MS ESI (+): 527 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.68 (s, 1H), 9.69 (brs, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 7.95 (s, 1H), 7.68 (s, 1H), 7.42 (s, 1H), 6.87 (s, 1H), 6.54-6.58 (m, 2H), 2.95 (s, 3H), 2.34 (s, 3H)

Example 488 Synthesis of 4-bromo-N-(3-chloro-5-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 3-chloro-5-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)aniline

The synthesis procedure of Intermediate 33 was repeated except for using 1-chloro-3-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)-5-nitrobenzene (125.4 mg, 0.36 mmol) to obtain 3-chloro-5-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)aniline (102.4 mg, 89%) as a yellow solid.

LC/MS ESI (+): 318 (M+1)

¹H-NMR (400 MHz, CDCl₃): δ 6.65 (m, 1H), 6.58 (s, 1H), 6.56 (m, 1H), 6.53 (s, 1H), 6.49 (m, 1H), 6.36 (m, 1H), 4.48 (m, 1H), 3.62 (s, 2H), 2.27 (s, 3H), 1.58 (s, 6H), 1.30 (d, 6H, J=6.1 Hz)

(b) Synthesis of N-(3-chloro-5-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 3-chloro-5-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)aniline (102.4 mg, 0.32 mmol) to obtain N-(3-chloro-5-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (140.3 mg, 76%) as an off-white solid.

LC/MS ESI (+): 571 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.94 (s, 1H), 8.28 (s, 1H), 8.00 (d, 1H, J=8.7 Hz), 7.88 (s, 1H), 7.77 (m, 1H), 7.52 (s, 1H), 7.34 (dd, 1H, J=8.7, 1.9 Hz), 7.00 (s, 1H), 6.60 (s, 1H), 6.58 (s, 1H), 6.48 (s, 1H), 4.53 (m, 1H), 2.99 (s, 3H), 2.24 (s, 3H), 1.61 (s, 6H), 1.22 (d, 6H, J=6.0 Hz)

(c) Synthesis of 4-bromo-N-(3-chloro-5-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

To a solution of N-(3-chloro-5-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (50.0 mg, 0.09 mmol) in anhydrous 1,4-dioxane (2.0 mL), NBS (15.6 mg, 0.09 mmol) and AIBN (2.8 mg, 0.02 mmol) were added at room temperature. The reaction mixture was heated at 80° C. for 4 hours, water was added at room temperature, followed by extracting with EtOAc. The organic extract was washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH₂Cl₂:MeOH=95:5) to obtain 4-bromo-N-(3-chloro-5-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (23.0 mg, 40%) as a white solid.

LC/MS ESI (+): 649 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.78 (s, 1H), 9.61 (s, 1H), 8.48 (s, 1H), 8.08 (d, 1H, J=8.7 Hz), 7.89 (s, 1H), 7.54-7.56 (m, 2H), 7.02 (s, 1H), 6.61 (s, 1H), 6.58 (s, 1H), 6.49 (s, 1H), 4.53 (m, 1H), 3.08 (s, 3H), 2.24 (s, 3H), 1.62 (s, 6H), 1.22 (d, 6H, J=6.0 Hz).

Example 489 Synthesis of N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[L]thiophene-2-carboxamide (a) Synthesis of 2-chloro-6-(4-chlorophenoxy)pyridin-4-amine

2,6-Dichloropyridin-4-amine (2.0 g, 12.27 mmol) and 4-chlorophenol (3.2 g, 24.54 mmol) were dissolved in anhydrous DMSO (123.0 mL), and K₂CO₃ (3.4 g, 24.54 mmol) was added, followed by stirring at 150° C. for 2 days. After cooling to room temperature, a saturated NH₄Cl aqueous solution (15.0 mL) was added to the reaction mixture. Then, the reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (C18-silica gel, 0.1% formic acid in CH₃CN:0.1% formic acid in H₂O=65:35), purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain 2-chloro-6-(4-chlorophenoxy)pyridin-4-amine (690.0 mg, 22%) as a white solid.

LC/MS ESI (+): 255 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 7.32 (d, 2H, J=8.8 Hz), 7.05 (d, 2H, J=8.8 Hz), 6.33 (d, 1H, J=1.6 Hz), 5.91 (d, 1H, J=1.6 Hz), 4.29 (brs, 2H)

(b) Synthesis of 5-(methylsulfonamido)benzo[b]thiophene-2-carbonyl chloride

5-(Methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (300.0 mg, 1.11 mmol) was dissolved in anhydrous CH₂Cl₂ (10.0 mL), and oxalyl chloride (0.15 mL, 1.66 mmol) and a catalytic amount of anhydrous DMF were added. After stirring at 110° C. for 30 minutes, the reaction mixture was cooled to room temperature and dried for 1 hour under reduced pressure. 320.0 mg of 5-(methylsulfonamido)benzo[b]thiophene-2-carbonyl chloride was obtained as a yellow liquid.

(c) Synthesis of N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

5-(Methylsulfonamido)benzo[b]thiophene-2-carbonyl chloride (39.0 mg, 0.14 mmol) and 2-chloro-6-(4-chlorophenoxy)pyridin-4-amine (23.0 mg, 0.09 mmol) were dissolved in anhydrous 1,4-dioxane (0.3 mL), followed by stirring at 75° C. for 15 hours. The residue was extracted with EtOAc, and the organic extract was washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=2:1) to obtain N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (15.0 mg, 33%) as a white solid.

LC/MS ESI (+): 508 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 10.90 (brs, 1H), 9.98 (brs, 1H), 8.33 (s, 1H), 8.05 (d, 1H, J=8.8 Hz), 7.83 (d, 1H, J=1.6 Hz), 7.67 (s, 1H), 7.53 (d, 2H, J=8.8 Hz), 7.83 (dd, 1H, J=4.4, 1.0 Hz), 7.32 (s, 1H), 7.26 (d, 2H, J=8.8 Hz), 3.02 (s, 3H)

Through the synthetic method according to Example 489, compounds from Example 490 to Example 492 were synthesized, and the data of each example are as follows.

TABLE 35 Ex. Compound Analysis data 490 6-chloro-N-(2-chloro-6-(4- LC/MS ESI (+): 542 (M + 1) chlorophenoxy)pyridin-4-yl)-5- ¹H-NMR (400 MHz, DMSO-d₆): δ 11.08 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 9.69 (brs, 1H), 8.33 (d, 2H, J = 6.4 Hz), 8.06 (s, 1H), 2-carboxamide 7.67 (s, 1H), 7.53 (d, 2H, J = 8.8 Hz), 7.31 (s, 1H), 7.27 (d, 2H, J = 8.8 Hz), 3.03 (s, 3H) 491 N-(2-chloro-6-((6- LC/MS ESI (+): 509 (M + 1) chloropyridin-3- ¹H-NMR (400 MHz, DMSO-d₆): δ 11.03 (brs, 1H), yl)oxy)pyridin-4-yl)-5- 9.86 (brs, 1H), 8.41 (d, 1H, J = 2.9 Hz), 8.35 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 8.05 (d, 1H, J = 8.7 Hz), 7.82~7.85 (m, 2H), 7.68 (d, 2-carboxamide 1H, J = 1.4 Hz), 7.64 (d, 1H, J = 8.7 Hz), 7.45 (d, 1H, J = 1.4 Hz), 7.38 (dd, 1H, J = 8.7, 2.1 Hz), 3.05 (s, 3H) 492 6-chloro-N-(2-chloro-6-((6- LC/MS ESI (+): 543 (M + 1) chloropyridin-3- ¹H-NMR (400 MHz, DMSO-d₆): δ 11.19 (brs, 1H), yl)oxy)pyridin-4-yl)-5- 9.66 (brs, 1H), 8.40 (d, 1H, J = 2.9 Hz), 8.33 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 8.32 (s, 1H), 8.05 (s, 1H), 7.83 (dd, 1H J = 8.7, 2-carboxamide 3.0 Hz), 7.67 (d, 1H, J = 1.2 Hz), 7.64 (d, 1H, J = 8.7 Hz), 7.43 (d, 1H, J = 1.2 Hz), 3.01 (s, 3H)

Example 493 Synthesis of N-(2-chloro-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 2-chloro-4-iodo-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridine

2,6-Dichloro-4-iodopyridine (500.0 mg, 1.83 mmol) and 6-(trifluoromethyl)pyridin-3-ol (298.0 mg, 1.83 mmol) were dissolved in anhydrous DMF (9.1 mL), and K₂CO₃ (378.0 mg, 2.74 mmol) was added, followed by stirring at 100° C. for 3 hours. After cooling to room temperature, the reaction mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:EtOAc=9:1) to obtain 2-chloro-4-iodo-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridine (170.0 mg, 23%) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ 8.60 (s, 1H), 7.69-7.77 (m, 2H), 7.51 (s, 1H), 7.38 (s, 1H)

(b) Synthesis of 2-chloro-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-4-amine

The synthesis procedure of Example 337-b was repeated except for using 2-chloro-4-iodo-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridine (230.0 mg, 0.57 mmol) to obtain 2-chloro-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-4-amine (90.0 mg, 54%) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ 8.56 (s, 1H), 7.64-7.75 (m, 2H), 6.40 (s, 1H), 6.12 (s, 1H), 4.41 (brs, 2H)

(c) Synthesis of N-(2-chloro-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 489-c was repeated except for using 2-chloro-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-4-amine (26.0 mg, 0.09 mmol) to obtain N-(2-chloro-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (17.8 mg, 37%) as a white solid.

LC/MS ESI (+): 543 (M+1)

¹H-NMR (400 MHz, DMSO-d₆): δ 11.03 (brs, 1H), 9.86 (brs, 1H), 8.69 (d, 1H, J=2.4 Hz), 8.30 (s, 1H), 7.95-8.01 (m, 3H), 7.79 (d, 1H, J=2.0 Hz), 7.65 (d, 1H, J=1.4 Hz), 7.46 (d, 1H, J=1.4 Hz), 7.33 (dd, 1H, J=8.7, 2.1 Hz), 2.97 (s, 3H).

Through the synthetic method according to Example 493, compounds from Example 494 to Example 496 were synthesized, and the data of each example are as follows.

TABLE 36 Ex. Compound Analysis data 494 6-chloro-N-(2-chloro-6-((6- LC/MS ESI (+): 577 (M + 1) (trifluoromethyl)pyridin-3- ¹H-NMR (400 MHz, DMSO-d₆): δ 11.19 (brs, 1H), yl)oxy)pyridin-4-yl)-5- 9.66 (brs, 1H), 8.74 (d, 1H, J = 2.4 Hz), 8.38 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 8.36 (s, 1H), 8.10 (s, 1H), 8.00~8.06 (m, 2H), 2-carboxamide 7.70 (d, 1H, J = 1.4 Hz), 7.51 (d, 1H, J = 1.4 Hz), 3.07 (s, 3H) 495 N-(2-chloro-6-(4- LC/MS ESI (+): 542 (M + 1) (trifluoromethyl)phenoxy)pyridin- ¹H-NMR(400 MHz, DMSO-d₆): δ 11.07 (brs, 1H), 4-yl)-5- 9.93 (brs, 1H), 8.35 (s, 1H), 8.06 (d, 1H, J = 8.8 Hz), (methylsulfonamido)benzo[b]thiophene- 7.85~7.87 (m, 3H), 7.72 (s, 1H), 7.39~7.46 (m, 4H), 2-carboxamide 3.03 (s, 3H) 496 6-chloro-N-(2-chloro-6-(4- LC/MS ESI (+): 576 (M + 1) (trifluoromethyl)phenoxy)pyridin- ¹H-NMR(400 MHz, DMSO-d₆): δ 11.14 (brs, 1H), 4-yl)-5- 9.68 (brs, 1H), 8.35~8.37 (m, 2H), 8.09 (s, 1H), (methylsulfonamido)benzo[b]thiophene- 7.86 (d, 2H, J = 8.4 Hz), 7.72 (d, 1H, J = 1.6 Hz), 7.45 (d, 2-carboxamide 2H, J = 8.4 Hz), 7.42 (d, 1H, J = 1.6 Hz), 3.07 (s, 3H)

Example 497 Synthesis of N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (a) Synthesis of 2-fluoro-4-methoxy-5-nitrobenzaldehyde

2-Fluoro-4-methoxybenzaldehyde (1.0 g, 6.49 mmol) was dissolved in concentrated H₂SO₄ (6.0 mL), and a 70% HNO₃ aqueous solution (0.8 mL, 6.49 mmol) and concentrated H₂SO₄ (0.8 mL, 14.92 mmol) were slowly added at −15° C., followed by stirring for 2 hours. The reaction mixture was poured in ice water, and the precipitate was filtered, dissolved in CH₂Cl₂, and neutralized with a saturated NaHCO₃ aqueous solution. An organic layer was dried over anhydrous Na₂SO₄, concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n-Hex:CH₂Cl₂=3:1) to obtain 2-fluoro-4-methoxy-5-nitrobenzaldehyde (1.2 g, 91%) as a white solid.

¹H-NMR (400 MHz, CDCl₃): δ 10.21 (s, 1H), 8.46 (d, 1H, J=7.2 Hz), 6.88 (d, 1H, J=11.6 Hz), 4.06 (s, 3H)

(b) Synthesis of methyl 6-methoxy-5-nitrobenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 26-a was repeated except for using 2-fluoro-4-methoxy-5-nitrobenzaldehyde (1.2 g, 5.93 mmol) to obtain methyl 6-methoxy-5-nitrobenzo[b]thiophene-2-carboxylate (1.3 g, 81%) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃): δ 8.34 (s, 1H), 8.03 (s, 1H), 7.47 (s, 1H), 4.04 (s, 3H), 3.96 (s, 3H)

(c) Synthesis of methyl 5-amino-6-methoxybenzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 13-b was repeated except for using methyl 6-methoxy-5-nitrobenzo[b]thiophene-2-carboxylate (1.3 g, 4.83 mmol) to obtain methyl 5-amino-6-methoxybenzo[b]thiophene-2-carboxylate (1.1 g, 93%) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃): δ 7.84 (s, 1H), 7.17 (s, 1H), 7.12 (s, 1H), 3.95 (brs, 5H), 3.91 (s, 3H)

(d) Synthesis of methyl 6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate

The synthesis procedure of Intermediate 6-a was repeated except for using methyl 5-amino-6-methoxybenzo[b]thiophene-2-carboxylate (200.0 mg, 0.84 mmol) to obtain methyl 6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (266.0 mg, 100%) as a yellow solid.

¹H-NMR (400 MHz, CDCl₃): δ 8.00 (s, 1H), 7.96 (s, 1H), 7.32 (s, 1H), 6.89 (s, 1H), 3.99 (s, 3H), 3.94 (s, 3H), 2.98 (s, 3H)

(e) Synthesis of 6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid

The synthesis procedure of Intermediate 6-b was repeated except for using methyl 6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylate (266.0 mg, 0.84 mmol) to obtain 6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (246.0 mg, 97%) as a white solid.

¹H-NMR (300 MHz, DMSO-d₆): δ 13.33 (brs, 1H), 9.08 (brs, 1H), 8.02 (s, ¹H), 7.86 (s, 1H), 7.72 (s, 1H), 3.91 (s, 3H), 2.98 (s, 3H)

(f) Synthesis of N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide

The synthesis procedure of Example 1 was repeated except for using 6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxylic acid (50.0 mg, 0.17 mmol) to obtain N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide (22.1 mg, 24%) as a white solid.

LC/MS ESI (+): 563 (M+1)

¹H-NMR (400 MHz, DMSO-d₆); δ 10.48 (brs, 1H), 9.11 (brs, 1H), 8.22 (s, 1H), 7.88 (m, 1H), 7.81 (s, 1H), 7.74 (s, 1H), 7.50 (m, 1H), 7.38 (d, 2H, J=8.7 Hz), 7.28 (d, 2H, J=8.7 Hz), 7.02 (m, 1H), 3.92 (s, 3H), 2.97 (s, 3H), 1.65 (s, 6H)

Through the synthetic method according to Example 497, a compound of Example 498 was synthesized, and the data of the example are as follows.

TABLE 37 Ex. Compound Analysis data 498 N-(3-chloro-5-(4- LC/MS ESI (+): 537 (M + 1) chlorophenoxy)phenyl)-6- ¹H-NMR(400 MHz, DMSO-d₆): δ 10.53 (brs, 1H), methoxy-5- 9.12 (brs, 1H), 8.19 (s, 1H), 7.81 (s, 1H), 7.75 (m, (methylsulfonamido)benzo[b]thiophene- 1H), 7.72 (m, 1H), 7.52 (d, 2H, J = 8.9 Hz), 7.36 (m, 2-carboxamide 1H), 7.19 (d, 2H, J = 8.9 Hz), 6.91 (m, 1H), 3.91 (s, 3H), 2.95 (s, 3H)

EXPERIMENTAL EXAMPLES

Experiments were performed as shown below for the compounds prepared in Examples above.

Experimental Example 1 Experiment on the Inhibition of STAT3 and STAT1 activities via reporter gene assay

1-1) Experiment on the Inhibition of STAT3 Activity

A human prostate cancer cell line (LNCaP stable cell line; plasmid pSTAT3-TA-luc), which contains a stably operating STAT3 promoter, was cultured in RPMI1640 medium (Cat No. 11875, Life Technologies) containing 10% fetal bovine serum (FBS) (Cat No. SH30396, Thermo Scientific) and 150 μg/mL G-418 solution (Cat No. 04 727 894 001, Roche). The reporter gene assay using LNCaP stable cell line was performed in RPMI1640 medium containing 3% DCC-FBS without G-418 solution. LNCaP stable cells were plated in two (2) white 96-well plates with 30,000 cells/50 μL in each well. The cells were cultured at 37° C., under 5% CO₂ for 24 hours, and then treated with the compounds listed in Examples which were diluted in various concentrations. Subsequently, IL-6 was added to each well with a final concentration of 10 ng/mL. Upon completion of the treatment with the compounds and IL-6, the cells were cultured at 37° C., under 5% CO₂ for from 24 to 48 hours. The plates were observed under microscope and drug precipitation and particular findings were investigated and recorded.

The luciferase assay and the cell viability assay were performed respectively with one of the two plates. For the luciferase assay, the liquid media in the 96-well plate was removed, and then, 20 μL of passive cell lysis buffer was added to each well. After shaking the plate for 30 minutes, luciferase activities of each well were measured in a PHERAstar™ microplate reader (BMG LABTECH) using a luciferase assay system (Cat No. E1501, Promega). For the cell viability assay, the 96-well plate was placed at room temperature for 30 minutes, added with 20 μL/well of CellTiter-Glo solution (Cat No. G7573, Promega), and shaken for 10 minutes in order to measure cytotoxicity caused by the compounds listed in Examples with a PHERAstar™ microplate reader (BMG LABTECH). Wells without 0.1% DMSO and stimulation were used as a negative control and wells with 0.1% DMSO and stimulation were used as a positive control.

1-2) Experiment on the Inhibition of STAT1 Activity

A human osteosarcoma cell line (U2OS stable cell line; pGL4-STAT1-TA-luc), which contains a stably operating STAT1 promoter, was cultured in McCoy 5′A medium (Cat No. 16600, Life Technologies) containing 10% FBS (Cat No. SH30396, Thermo Scientific) and 1000 μg/mL G418 solution (Cat No. 04 727 894 001, Roche). The reporter gene assay using U2OS stable cell line was performed in McCoy 5′A medium containing 10% FBS without G-418 solution. U2OS stable cells were plated in two (2) white 96-well plates with 25,000 cells/50 μL in each well. The cells were cultured at 37° C., under 5% CO₂ for from 8 to 24 hours, and then treated with the compounds listed in Examples which were diluted in various concentrations. Subsequently, IFN-γ was added to each well with a final concentration of 50 ng/mL. Upon completion of the treatment with the compounds and IFN-γ, the cells were cultured at 37° C., under 5% CO₂ for 24 hours. The plates were observed under microscope and drug precipitation and particular findings were investigated and recorded.

The luciferase assay and the cell viability assay were performed respectively with one of two plates. For the luciferase assay, the liquid media in the 96-well plate was removed, and then, 20 μL of passive cell lysis buffer was added to each well. After shaking the plate for 30 minutes, luciferase activities of each well were measured in a PHERAstar™ microplate reader (BMG LABTECH) using a luciferase assay system (Cat No. E1501, Promega). For the cell viability assay, the 96-well plate was placed at room temperature for 30 minutes, added with 20 μL/well of CellTiter-Glo solution (Cat No. G7573, Promega), and shaken for 10 minutes in order to measure cytotoxicity caused by the compounds listed in Examples with a PHERAstar™ microplate reader (BMG LABTECH). Wells without 0.1% DMSO and stimulation were used as a negative control and wells with 0.1% DMSO and stimulation were used as a positive control.

The results of evaluation on the inhibitory effect of the compounds listed in the Examples on the dimerization of STAT3 and STAT1 obtained via the STAT3 and STAT1 reporter gene assays are shown in Table 38 below.

TABLE 38 IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) Example pSTAT3 pSTAT1 Example pSTAT3 pSTAT1 1 0.190 >10 2 0.200 >10 3 0.220 >10 4 0.340 >10 5 1.200 >10 6 >10 >10 7 0.310 >10 8 0.120 >10 9 0.056 >10 10 0.430 >10 11 0.200 >10 12 0.260 >10 13 0.220 >10 14 0.130 >10 15 0.120 >10 16 0.112 >10 17 0.140 >10 18 5.400 >10 19 0.120 >10 20 0.290 >10 21 0.220 >10 22 0.110 >10 23 0.045 >10 24 0.051 >10 25 3.300 >10 26 0.059 >10 27 0.080 >10 28 0.610 >10 29 0.530 >10 30 0.430 >10 31 0.190 >10 32 0.034 >10 33 0.035 >10 34 0.051 >10 35 0.076 >10 36 0.027 >10 37 0.046 >10 38 0.100 >10 39 0.048 >10 40 0.076 >10 41 0.028 >10 42 0.007 >10 43 2.700 >10 44 1.400 >10 45 1.300 >10 46 0.082 >10 47 0.008 >10 48 0.007 >10 49 0.007 >10 50 0.150 >10 51 0.550 >10 52 1.500 >10 53 0.026 >10 54 0.048 >10 55 0.160 >10 56 0.072 >10 57 0.067 >10 58 0.007 >10 59 0.021 >10 60 0.063 >10 61 0.066 >10 62 0.011 >10 63 0.034 >10 64 0.065 >10 65 0.064 >10 66 >10 >10 67 0.067 >10 68 0.011 >10 69 0.052 >10 70 0.068 >10 71 0.009 >10 72 0.021 >10 73 0.010 >10 74 2.700 >10 75 0.008 >10 76 3.000 >10 77 0.120 >10 78 0.017 >10 79 0.014 >10 80 0.016 >10 81 0.055 >10 82 0.024 >10 83 0.023 >10 84 0.004 >10 85 0.016 >10 86 0.072 >10 87 0.016 >10 88 0.015 >10 89 0.047 >10 90 0.043 >10 91 0.032 >10 92 0.067 >10 93 0.091 >10 94 1.120 >10 95 0.110 >10 96 3.400 8.7 97 2.100 >10 98 0.098 >10 99 0.220 >10 100 0.042 >10 101 0.280 >10 102 4.600 >10 103 0.110 >10 104 0.224 >10 105 0.005 >10 106 0.520 >10 107 0.420 >10 108 0.078 >10 109 0.078 >10 110 4.300 >10 111 >10 >10 112 6.800 >10 113 8.900 >10 114 0.020 >10 115 2.500 >10 116 0.053 >10 117 0.230 >10 118 >10 >10 119 >10 >10 120 0.660 >10 121 1.800 >10 122 0.120 >10 123 0.046 >10 124 4.000 >10 125 0.890 >10 126 0.100 >10 127 0.150 >10 128 0.270 >10 129 0.070 >10 130 0.308 >10 131 0.085 >10 132 0.350 >10 133 0.150 >10 134 0.270 >10 135 0.140 >10 136 0.059 >10 137 0.220 >10 138 0.020 >10 139 0.110 >10 140 0.090 >10 141 0.380 >10 142 0.130 >10 143 0.290 >10 144 5.200 >10 145 0.067 >10 146 0.073 >10 147 0.670 >10 148 >10 >10 149 0.070 >10 150 0.014 >10 151 2.200 >10 152 0.120 >10 153 0.150 >10 154 0.140 >10 155 0.078 >10 156 0.230 >10 157 0.063 >10 158 0.120 >10 159 0.310 >10 160 3.300 >10 161 >10 >10 162 0.069 >10 163 0.011 >10 164 0.720 >10 165 0.130 >10 166 0.310 >10 167 2.600 >10 168 0.130 >10 169 0.039 >10 170 0.068 >10 171 0.074 >10 172 0.016 >10 173 0.011 >10 174 0.100 >10 175 0.007 >10 176 0.036 >10 177 0.047 >10 178 0.025 >10 179 0.004 >10 180 0.010 >10 181 0.005 >10 182 0.012 >10 183 0.010 >10 184 0.042 >10 185 0.007 >10 186 0.100 >10 187 0.110 >10 188 0.054 >10 189 >10 >10 190 2.370 >10 191 0.540 >10 192 0.750 — 193 0.380 >10 194 >10 >10 195 0.011 >10 196 0.020 >10 197 0.012 >10 198 0.030 >10 199 0.650 >10 200 0.069 >10 201 0.029 >10 202 0.007 >10 203 0.006 >10 204 0.051 >10 205 0.300 >10 206 0.190 >10 207 3.000 >10 208 0.170 >10 209 0.043 >10 210 0.140 >10 211 0.007 >10 212 0.010 >10 213 0.018 >10 214 0.170 >10 215 0.002 >10 216 0.380 >10 217 2.060 >10 218 >10 >10 219 1.190 >10 220 0.012 >10 221 0.011 >10 222 6.100 5.0 223 0.240 2.3 224 0.260 >10 225 >10 >10 226 6.300 >10 227 >10 >10 228 >10 >10 229 1.400 >10 230 1.100 >10 231 2.900 >10 232 >10 >10 233 >10 >10 234 >10 >10 235 >10 >10 236 0.310 >10 237 0.110 >10 238 0.270 >10 239 >10 >10 240 >10 >10 241 1.800 >10 242 0.960 >10 243 7.200 >10 244 >10 >10 245 1.400 >10 246 8.400 >10 247 >10 6.2 248 6.100 >10 249 >10 >10 250 >10 >10 251 >10 >10 252 >10 >10 253 4.700 >10 254 >10 >10 255 >10 >10 256 >10 >10 257 3.500 >10 258 2.700 >10 259 1.100 >10 260 0.710 >10 261 2.400 >10 262 5.300 >10 263 >10 >10 264 1.900 >10 265 4.200 >10 266 6.800 >10 267 2.000 >10 268 >10 >10 269 2.300 >10 270 0.380 >10 271 5.900 >10 272 0.500 >10 273 2.200 >10 274 >10 >10 275 3.300 >10 276 3.100 >10 277 0.380 >10 278 4.500 >10 279 6.200 >10 280 1.700 >10 281 7.100 >10 282 >10 >10 283 7.400 >10 284 1.900 >10 285 2.500 >10 286 >10 >10 287 >10 >10 288 >10 >10 289 >10 >10 290 7.000 >10 291 3.200 >10 292 >10 >10 293 2.700 >10 294 2.600 >10 295 >10 >10 296 >10 >10 297 >10 >10 298 >10 >10 299 3.100 >10 300 5.300 >10 301 3.300 >10 302 0.400 >10 303 0.230 9.0 304 4.000 >10 305 0.067 >10 306 0.280 >10 307 1.100 >10 308 5.600 >10 309 1.500 >10 310 0.800 >10 311 5.700 >10 312 0.240 >10 313 3.600 >10 314 4.500 >10 315 2.600 >10 316 3.600 >10 317 0.280 >10 318 8.100 >10 319 >10 >10 320 6.200 >10 321 8.200 >10 322 0.028 >10 323 0.110 >10 324 0.530 >10 325 0.240 >10 326 0.100 >10 327 0.041 >10 328 0.340 >10 329 0.010 >10 330 0.029 >10 331 0.051 >10 332 0.061 >10 333 0.016 9.9 334 0.096 >10 335 5.700 >10 336 0.130 >10 337 0.270 >10 338 0.920 >10 339 0.760 1.9 340 >10 >10 341 3.300 >10 342 0.390 >10 343 1.800 >10 344 0.150 >10 345 1.600 >10 346 0.200 >10 347 1.500 >10 348 >10 >10 349 0.480 >10 350 1.500 >10 351 0.300 >10 352 0.820 8.8 353 0.760 >10 354 0.330 7.4 355 0.210 >10 356 3.600 >10 357 1.700 >10 358 1.700 >10 359 >10 >10 360 >10 >10 361 >10 >10 362 0.720 >10 363 1.300 >10 364 >10 >10 365 0.400 >10 366 1.200 >10 367 0.380 >10 368 2.700 >10 369 0.700 >10 370 0.210 >10 371 0.900 >10 372 0.340 >10 373 1.500 >10 374 6.400 >10 375 0.140 >10 376 5.200 >10 377 >10 >10 378 >10 >10 379 >10 >10 380 >10 >10 381 >10 >10 382 0.330 >10 383 0.090 2.3 384 >10 >10 385 4.300 >10 386 3.400 >10 387 2.400 >10 388 3.800 >10 389 5.800 >10 390 3.700 >10 391 2.400 >10 392 1.800 >10 393 >10 >10 394 3.300 >10 395 2.100 >10 396 2.500 >10 397 3.000 >10 398 1.600 >10 399 2.800 >10 400 3.200 >10 401 4.000 >10 402 6.300 >10 403 8.200 >10 404 >10 >10 405 2.400 >10 406 >10 >10 407 5.700 >10 408 2.400 >10 409 2.900 >10 410 3.100 >10 411 3.600 >10 412 3.400 >10 413 >10 >10 414 1.700 >10 415 6.800 >10 416 6.000 >10 417 >10 >10 418 0.840 >10 419 0.670 >10 420 0.820 >10 421 0.200 >10 422 0.760 >10 423 0.260 >10 424 0.150 >10 425 0.460 >10 426 0.082 >10 427 0.130 >10 428 1.000 >10 429 0.190 >10 430 0.012 >10 431 0.053 >10 432 0.049 >10 433 0.013 >10 434 6.500 >10 435 5.800 >10 436 5.200 >10 437 6.300 >10 438 0.200 >10 439 0.053 >10 440 0.036 >10 441 0.009 >10 442 0.021 >10 443 0.065 >10 444 0.083 >10 445 0.066 >10 446 0.096 >10 447 0.270 >10 448 0.230 >10 449 0.024 >10 450 0.100 >10 451 0.140 >10 452 0.079 >10 453 0.022 >10 454 0.120 >10 455 0.190 >10 456 0.190 >10 457 0.280 >10 458 0.250 >10 459 0.360 >10 460 0.150 >10 461 0.140 >10 462 0.130 >10 463 0.190 >10 464 0.170 >10 465 0.120 >10 466 0.120 >10 467 0.220 >10 468 0.170 >10 469 0.360 >10 470 0.320 >10 471 0.075 >10 472 0.100 >10 473 0.100 >10 474 0.048 >10 475 >10 >10 476 0.021 >10 477 0.025 >10 478 0.022 >10 479 0.014 >10 480 0.019 >10 481 0.015 >10 482 0.016 >10 483 0.014 >10 484 0.021 >10 485 0.129 >10 486 0.110 >10 487 0.059 >10 488 0.350 >10 489 0.110 >10 490 0.016 >10 491 0.130 >10 492 0.008 >10 493 0.140 >10 494 0.018 >10 495 0.080 >10 496 0.009 >10 497 0.005 >10 498 0.060 >10

As shown in Table 38, the compounds according to the present invention exhibited excellent inhibitory effects against the activity of STAT3 protein but showed almost no inhibitory effect against the activity of STAT1 protein.

Experimental Example 2 Cell Growth Inhibition Assay

The inhibitory effects of the compounds of the present invention against the growth of cancer cells were evaluated as shown below. The cancer cell lines including stomach cancer cell line (AGS), breast cancer cell lines (MDA-MB-231, MDA-MB-468, and BT-549), prostate cancer cell lines (LNCaP and DU-145), colon cancer cell line (HCT116), ovarian cancer cell line (SW626), liver cancer cell line (Hep3B), kidney cancer cell line (ACHN), lung cancer cell line (NCI-H23) and blood cancer cell lines (HEL92.1.7 and U266) were cultured under the protocol provided by each supplier. A medium supplemented with 10 ng/mL of IL-6 was used for LNCaP, a prostate cancer cell line, when treated with a drug. Each type of cells to be used in experiments were sub-cultured in a 96-well plate by counting the exact number of cells using Tali™ Image-based Cytometer (Life Technologies). In a 96-well plate, AGS, HCT116, and DU-145 were employed with 3,000 cells/well; NCI-H23, SW626, Hep3B, ACHN, BT-549, MDA-MB-231, HEL92.1.7, and U266 were employed with 5,000 cells/well; and LNCaP and MDA-MB-468 were employed with 10,000 cells/well. The cells were treated with the compounds listed in Examples which were diluted in various concentrations. Upon completion of the compounds treatment, AGS, HCT116, SW626, DU145, NCI-H23, Hep3B, ACHN, BT-549, LNCaP, HEL92.1.7, and U266 cells were cultured at 37° C. under 5% CO₂ for from 72 to 96 hours, and MDA-MB-231 and MDA-MB-468 cells were cultured at 37° C. in air for from 72 to 96 hours. Subsequently, the cells were observed under microscope and drug precipitation and particular findings were investigated and recorded. And then, the 96-well plate was placed at room temperature for 30 minutes, added with 20 μL/well of CellTiter-Glo solution (Cat No. G7573, Promega) and shaken for 10 minutes, followed by being subjected to the measurement using PHERAstar™ microplate reader (BMG LABTECH) according to the supplier's general luminometer protocol. Wells where only culture liquid added without cell plating were used as a negative control, whereas wells where culture liquid containing 0.1% DMSO instead of the compounds listed in Examples were used as a positive control.

The results of the inhibitory effects of the compounds prepared in Examples against the growth of cancer cells are shown in Tables 39 to 46 below.

TABLE 39 IC₅₀ IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) (μM) Ex. LNCap Ex. LNCap Ex. LNCap Ex. LNCap 1 2.500 2 5.300 3 1.100 4 0.820 5 4.700 6 >10 7 2.400 8 0.870 9 0.780 10 1.700 11 1.800 12 1.400 13 0.480 14 0.550 15 0.290 16 0.480 17 0.920 18 9.600 19 0.520 20 1.100 21 0.900 22 0.290 23 0.170 24 0.083 25 4.200 26 0.360 27 0.670 28 4.700 29 3.800 30 2.900 31 0.490 32 0.150 33 0.150 34 0.240 35 0.067 36 0.210 37 0.390 38 0.800 39 0.220 40 0.370 41 0.110 42 0.032 43 5.800 44 5.200 45 4.400 46 0.130 47 0.031 48 0.077 49 0.049 50 0.760 51 3.500 52 4.700 53 0.070 54 0.170 55 0.540 56 0.250 57 0.160 58 0.032 59 0.120 60 0.370 61 0.130 62 0.075 63 0.037 64 0.100 66 >1.1 67 0.037 68 0.019 69 0.058 70 0.290 71 0.091 72 0.034 73 0.033 74 6.600 75 0.029 76 0.230 77 0.300 78 0.038 79 0.039 80 0.068 81 0.150 82 0.030 83 0.025 84 0.008 85 0.025 86 0.075 87 0.028 88 0.024 89 0.070 90 0.220 91 0.056 92 0.071 93 0.055 94 0.270 95 0.015 96 >1.1 98 0.760 99 1.500 100 >10 101 1.100 103 0.035 104 0.420 105 0.002 106 0.110 107 1.200 108 0.310 109 0.420 110 >10 111 >10 112 8.600 113 >10 114 0.061 115 5.600 116 0.220 117 2.600 118 >10 119 >10 120 3.600 121 3.700 122 0.240 123 0.150 124 6.500 125 2.100 126 0.110 127 0.140 128 0.410 129 0.120 130 0.760 131 0.260 132 0.970 133 0.700 134 0.840 135 0.850 136 0.380 137 0.400 138 0.054 139 0.170 140 0.130 141 0.360 142 0.330 143 0.470 144 2.600 145 0.040 146 0.022 147 0.800 148 0.580 149 0.050 150 0.016 151 0.360 152 0.059 153 0.100 154 0.110 155 0.034 156 0.140 157 0.079 158 0.056 159 0.160 160 >1.1 161 >1.1 162 0.064 163 0.013 164 0.900 165 0.110 166 1.000 167 2.300 168 0.096 169 0.073 170 0.059 171 0.071 172 0.009 173 0.110 174 0.091 175 0.016 176 0.071 177 0.089 178 0.042 179 0.007 180 <0.005 181 0.006 182 0.018 183 0.013 184 0.350 185 0.072 186 0.039 187 0.100 188 0.056 189 >10 190 >1.1 191 2.200 193 0.990 194 >1.1 195 0.035 196 0.084 197 0.065 198 0.046 199 0.340 200 0.280 201 0.064 202 0.014 203 0.023 204 0.095 205 0.310 206 0.190 207 >1.1 208 0.220 209 0.053 210 0.280 211 0.050 212 0.075 213 0.025 214 0.990 215 0.006 216 1.100 217 >1.1 218 7.700 219 0.190 220 0.013 221 0.011 222 >1.1 223 0.170 224 0.270 225 >10 226 >10 227 >10 228 >10 229 5.400 230 2.700 231 >10 232 >10 233 >10 234 1.560 235 >10 236 2.700 237 0.610 238 2.400 239 8.300 240 >10 241 5.400 242 4.000 243 6.400 244 >10 245 4.900 246 9.200 247 3.700 248 9.600 249 >10 250 >10 251 >10 252 >10 253 8.500 254 >10 255 >10 256 >10 257 2.800 258 5.200 259 2.000 260 4.100 261 2.900 262 9.800 263 8.000 264 6.200 265 >10 266 >10 267 3.200 268 >10 269 4.100 270 1.010 271 8.600 272 2.600 273 4.100 274 >10 275 9.000 276 1.300 277 1.800 278 5.900 279 >10 280 2.700 281 >10 282 >10 283 >10 284 3.100 285 3.300 286 >10 287 >10 288 >10 289 >10 290 >10 291 8.100 292 >10 293 4.600 294 3.500 295 >10 296 >10 297 8.600 298 >10 299 >10 300 >10 301 3.900 302 2.500 303 0.720 304 >10 305 0.072 306 1.700 307 4.800 308 >10 309 5.900 310 3.200 311 6.700 312 1.300 313 3.700 314 3.700 315 3.000 316 7.000 317 0.370 318 >10 319 >10 320 >10 321 >10 322 0.021 323 0.063 324 0.480 325 0.160 326 0.140 327 0.088 328 0.340 329 0.008 330 0.011 331 0.150 332 0.170 333 0.015 334 0.140 335 >1.1 336 0.210 337 0.940 338 >1.1 339 0.560 340 >1.1 341 6.200 342 5.000 343 2.800 344 0.014 345 3.500 346 0.463 347 7.900 348 7.200 349 2.300 350 6.500 351 >10 352 7.600 353 2.400 354 5.700 355 1.800 356 9.900 357 6.600 358 8.000 359 >10 360 >10 361 >10 362 2.600 363 2.400 364 >10 365 2.800 366 6.200 367 7.400 368 9.800 369 3.800 370 0.600 371 7.800 372 3.500 373 4.400 374 9.900 375 1.100 376 7.700 377 >10 378 >10 379 >10 380 >10 381 >10 382 3.800 383 4.300 384 >10 385 >10 386 8.000 387 3.500 388 8.200 389 9.100 390 2.500 391 >10 392 8.300 393 >10 394 >10 395 >10 396 8.900 397 5.800 398 2.600 399 >10 400 >10 401 8.000 402 >10 403 >10 404 >10 405 8.600 406 >10 407 >10 408 >10 409 >10 410 >10 411 >10 412 >10 413 >10 414 9.600 415 >10 416 9.000 417 >10 418 1.600 419 1.000 420 1.700 421 1.100 422 2.100 423 1.100 424 0.500 425 1.300 426 0.300 427 0.410 428 1.400 429 0.350 430 0.006 431 0.034 432 0.073 433 0.010 434 >10 435 >10 436 >10 437 >10 438 0.420 439 0.150 440 0.021 441 0.012 442 0.036 443 0.039 444 0.240 445 0.074 446 0.130 447 0.490 448 0.350 449 0.022 450 0.099 451 0.510 452 0.330 453 0.350 454 0.830 455 0.220 456 0.300 457 0.370 458 0.330 459 0.790 460 0.230 461 0.240 462 0.330 463 0.270 464 0.310 465 0.063 466 0.079 467 0.039 468 0.040 469 0.120 470 0.067 471 0.110 472 0.370 473 0.015 474 0.059 475 >1.1 476 0.022 477 0.013 478 0.018 479 0.008 480 0.010 481 0.036 482 0.013 483 0.020 484 0.037 485 >1.1 486 0.083 487 0.036 488 2.500 489 0.110

TABLE 40 IC₅₀ IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) (μM) MDA- MDA- MDA- MDA- Ex. MB-231 Ex. MB-231 Ex. MB-231 Ex. MB-231 1 0.230 2 0.140 3 0.090 4 0.052 5 1.200 6 >10 7 0.350 8 0.018 9 0.012 10 0.180 11 0.060 12 0.034 13 0.030 14 0.062 15 0.068 16 0.025 17 0.190 18 8.700 19 0.088 20 0.150 21 0.054 22 0.007 23 0.028 24 0.027 25 3.200 26 0.008 27 0.033 28 1.000 29 0.470 30 0.370 31 0.026 32 0.021 33 0.003 34 0.007 35 0.027 36 0.005 37 0.016 38 0.049 39 0.050 40 0.006 41 0.024 42 0.005 43 3.600 44 4.000 45 0.380 46 0.029 47 0.006 48 0.002 49 0.001 50 0.240 51 0.620 52 0.700 53 0.022 54 0.036 55 0.081 68 0.041 98 0.590 107 0.290 108 0.073 109 0.090 110 3.300 111 6.300 112 >10 113 6.400 115 1.500 116 0.055 117 2.200 118 8.600 119 6.100 224 0.033 236 0.410 237 0.010 238 0.550 239 >10 240 >10 241 2.700 242 0.540 243 1.600 245 2.600 246 3.500 260 0.920 269 2.100 270 0.700 275 >10 293 1.000 301 0.720 302 0.110 303 0.020 304 5.300 305 0.001 306 0.370 307 0.840 308 8.100 309 1.200 310 0.390 311 1.000 312 0.220 313 0.140 314 0.370 316 4.600 317 0.019 318 >10 319 >10 320 >10 321 >10 341 7.500 342 0.520 344 0.100 346 0.180 347 0.610 348 >10 349 0.320 350 2.300 351 9.900 352 2.400 353 0.440 354 0.710 355 0.280 356 3.300 357 1.200 358 1.200 359 2.600 360 1.800 361 >10 362 0.690 363 0.880 364 >10 365 0.320 366 0.580 367 1.100 368 1.700 369 0.280 370 0.032 371 1.400 372 0.460 373 1.000 374 2.700 375 0.028 376 1.300 382 0.910 383 2.330 384 >10 387 1.170 390 1.100 391 3.300 393 5.000 395 4.200 396 1.200 397 2.800 398 1.200 399 3.400 400 3.500 401 2.500 415 8.400 416 2.600 417 >10 421 0.089 422 0.540 423 0.094 424 0.100 425 0.380 426 0.074 427 0.085 428 0.390 429 0.086 434 2.900 435 4.300 436 4.700 437 >10

TABLE 41 IC₅₀ IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) (μM) Ex. AGS Ex. AGS Ex. AGS Ex. AGS 16 0.044 36 0.009 225 >50 226 6.9 227 30.0 228 41.4 229 16.1 230 17.6 231 19.3 232 20.5 233 >50 234 1.6 235 37.0 244 30.6 247 >50 248 15.7 249 8.4 250 22.0 251 26.7 252 11.4 253 7.6 254 >50 255 18.1 256 >50 257 11.0 258 16.3 260 2.7 261 28.4 262 >50 263 >50 264 13.0 265 11.4 266 8.5 267 9.2 268 27.1 271 26.1 272 18.8 273 10.0 274 17.9 275 5.7 276 11.9 277 2.1 278 20.0 279 40.7 280 2.7 281 16.6 282 23.8 283 18.2 284 11.3 285 13.6 286 10.2 287 23.6 288 >50 289 32.0 290 20.9 291 13.9 292 43.7 293 24.6 294 16.1 295 >50 296 >50 297 21.6 298 31.7 299 43.1 300 >50 301 5.7 315 25.9 341 5.3 342 9.6 343 5.8 345 6.9 347 19.7 348 4.8 366 8.9 367 9.5 368 11.5 377 15.2 378 39.9 379 30.1 380 42.6 381 >50 385 26.3 386 7.6 388 9.8 389 20.3 390 9.6 391 18.1 392 9.0 393 10.3 394 20.0 395 20.6 396 11.8 397 8.7 398 5.2 399 13.2 400 14.9 401 7.3 402 22.1 403 34.4 404 30.3 405 14.6 406 17.6 407 45.5 408 24.2 409 17.3 410 31.3 411 35.2 412 22.0 413 >50 414 14.4

TABLE 42 IC₅₀ IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) (μM) Ex. DU-145 Ex. DU-145 Ex. DU-145 Ex. DU-145 9 0.035 15 0.250 16 0.024 19 0.150 21 0.190 22 0.048 24 0.044 32 0.044 33 0.037 34 0.023 35 0.060 36 0.006 42 0.009 43 4.900 48 0.008 49 0.007 50 0.360 54 0.046 56 0.069 57 0.047 58 0.006 59 0.039 60 0.170 61 0.060 62 0.016 63 0.010 64 0.043 65 0.005 66 >1.1 67 0.042 68 0.006 69 0.052 70 0.120 71 0.048 72 0.006 73 0.006 74 2.600 75 0.003 76 0.340 77 0.050 78 0.009 79 0.008 80 0.010 81 0.110 82 0.008 83 0.012 84 0.002 85 0.007 86 0.047 87 0.009 88 0.008 89 0.048 90 0.048 91 0.012 92 0.017 93 0.021 94 0.200 95 0.011 96 >1.1 97 0.170 98 0.310 99 0.800 100 0.330 101 0.440 102 >1.1 103 0.045 104 0.580 105 0.001 106 0.031 114 0.014 115 1.700 116 0.058 117 1.200 120 2.200 121 0.710 122 0.049 123 0.042 124 2.100 125 0.460 126 0.110 127 0.066 128 0.150 129 0.060 130 0.170 131 0.100 132 0.410 133 0.220 134 0.160 135 0.300 136 0.051 137 0.100 138 0.018 139 0.073 140 0.053 141 0.140 142 0.090 143 0.180 144 1.000 145 0.060 146 0.019 147 0.470 148 0.380 149 0.030 150 0.008 151 >1.1 152 0.047 153 0.150 154 0.170 155 0.061 156 0.250 157 0.060 158 0.048 159 0.140 160 >1.1 161 0.720 162 0.052 163 0.016 164 >1.1 165 0.070 166 0.410 167 >1.1 168 0.130 169 0.021 170 0.005 171 0.038 172 0.005 173 0.009 174 0.033 175 0.005 176 0.038 177 0.058 178 0.024 179 0.004 180 <0.005 181 0.005 182 0.005 183 0.005 184 0.040 185 0.007 186 0.023 187 0.042 188 0.026 189 >1.1 190 >1.1 191 0.740 193 0.390 194 >1.1 195 0.007 196 0.022 197 0.016 198 0.017 199 0.150 200 0.190 201 0.018 202 0.007 203 0.008 204 0.017 205 0.063 206 0.051 207 >1.1 208 0.080 209 0.027 210 0.073 211 0.014 212 0.022 213 0.011 214 0.300 215 0.002 216 0.300 217 0.580 218 >1.1 219 0.180 220 0.007 221 0.008 222 >1.1 223 0.005 302 0.570 305 0.030 322 0.011 323 0.035 324 0.400 325 0.150 326 0.064 327 0.034 328 0.390 329 0.004 330 0.005 331 0.034 332 0.042 333 0.004 334 0.059 335 >1.1 336 0.065 337 0.430 338 0.430 339 0.310 340 >1.1 346 0.370 418 0.980 419 0.650 420 0.950 426 0.130 430 0.006 431 0.038 432 0.060 433 0.006 438 0.160 439 0.089 440 0.012 441 0.026 442 0.013 443 0.020 444 0.130 445 0.055 446 0.065 447 0.140 448 0.160 449 0.010 450 0.060 451 0.190 452 0.027 453 0.018 454 0.059 455 0.190 456 0.250 457 0.440 458 0.170 459 0.590 460 0.130 461 0.110 462 0.130 463 0.150 464 0.160 465 0.048 466 0.063 467 0.048 468 0.028 469 0.086 470 0.043 471 0.049 472 0.130 473 0.015 474 0.022 475 >1.1 476 0.005 477 0.010 478 0.012 479 0.006 480 0.007 481 0.008 482 0.005 483 0.010 484 0.021 485 0.380 486 0.048 487 0.025 488 1.100 489 0.031

TABLE 43 IC₅₀ IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) (μM) Ex. U-266 Ex. U-266 Ex. U-266 Ex. U-266 9 0.740 16 0.250 22 0.130 24 0.130 34 0.290 36 0.220 42 0.023 48 0.044 49 0.014 50 0.840 56 0.430 57 0.330 58 0.005 59 0.160 61 0.220 68 0.019 69 0.140 70 0.460 71 0.170 72 0.100 73 0.058 75 0.021 77 0.220 80 0.063 82 0.045 98 0.560 116 0.160 122 0.180 123 0.130 127 0.430 129 0.280 130 0.740

TABLE 44 IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ Ex. HEL92.1.7 Ex. HEL92.1.7 Ex. HEL92.1.7 Ex. (μM) HEL92.1.7 9 0.950 15 1.800 16 0.140 22 0.130 24 0.120 34 0.200 35 0.280 36 0.270 42 0.044 48 0.026 49 0.023 50 0.830 56 0.300 57 0.180 58 0.074 59 0.420 61 0.140 64 0.110 66 >1.1 67 0.110 68 0.024 69 0.090 70 0.360 71 0.130 72 0.087 73 0.056 75 0.020 77 0.068 80 0.057 81 0.340 82 0.048 83 0.100 84 0.014 85 0.076 86 0.230 87 0.091 88 0.087 89 0.220 90 0.230 91 0.078 92 0.100 93 0.120 94 0.350 95 0.690 96 >1.1 98 0.860 103 0.160 116 0.130 122 0.190 123 0.110 127 0.340 129 0.240 130 >1.1 138 0.260 139 0.690 140 0.300 141 1.050 142 0.330 143 0.480 144 >1.1 145 0.160 146 0.320 147 1.040 148 1.000 149 0.140 150 0.031 151 4.700 152 0.210 153 0.390 154 0.340 155 0.130 156 0.740 157 0.230 158 0.220 162 0.200 163 0.019 164 >1.1 166 >1.1 167 >1.1 168 0.390 169 0.090 189 >1.1 190 >1.1 194 >1.1 195 0.029 196 0.120 199 0.680 200 0.300 201 0.053 202 0.013 203 0.017 204 0.050 205 0.580 206 0.350 207 >1.1 208 0.330 209 0.099 210 0.570 211 0.066 212 0.081 214 >1.1 215 0.007 216 0.950 217 >1.1 218 >1.1 219 0.900 270 1.700 302 2.700 305 0.240 322 0.049 323 0.097 324 0.830 325 0.390 326 0.260 327 0.082 328 0.500 329 0.009 330 0.057 344 0.490 346 1.300 418 2.200 419 1.800 420 2.400 430 0.014 431 0.007 438 0.480 439 0.640 440 0.085 444 0.650 445 0.150

TABLE 45 IC₅₀ (μM) IC₅₀ MDA- IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) IC₅₀ (μM) (μM) Ex. MB-468 ACHN HCT-116 Hep3B SW626 NCI-H23 BT-549 16 0.020 0.004 0.310 2.100 0.066 0.300 0.260 34 <0.00064 — — 0.028 — — 3.400 36 <0.0076 <0.00085 <0.072 2.200 0.013 <0.210 0.043 346 0.140 0.370 1.500 2.200 0.290 1.700 1.000

TABLE 46 IC₅₀ IC₅₀ (μM) IC₅₀ IC₅₀ (μM) IC₅₀ MDA- (μM) (μM) IC₅₀ IC₅₀ IC₅₀ NCI- (μM) IC₅₀ (μM) MB- NCI- NCI- (μM) (μM) (μM) Ex. H508 SW1417 HCC1500 361 H661 H1650 Raji IM-9 C-33A 346 0.22 0.35 1.03 0.28 0.09 0.62 0.57 0.51 0.30

As shown in Tables 39 to 46, the compounds according to the present invention exhibited excellent inhibitory effects against the growth of various kinds of cancer cells.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modifications and changes may be made to the invention by those skilled in the art which also fall within the scope of the invention as defined by the appended claims. 

1. A compound selected from the group consisting of a heterocyclic derivative represented by formula (I), and a pharmaceutically acceptable salt and a stereoisomer thereof:

wherein A is present or absent, and, if present, A is a saturated or unsaturated C₃₋₁₀ carbocycle or a 5- to 10-membered heterocycle, and if A is absent, X₃ and X₄ are each independently optionally substituted with R₁ or R₂; B is a benzene or a 5- to 12-membered heterocycle; C is a benzene, a 5- to 12-membered heterocycle, or C₃₋₆ carbocycle; Y is —C(═O)— connected to X₂ or X₅; X₁ is —O—, —S—, —S(═O)—, —S(═O)₂—, or —N(W₁)—; X₂ is a carbon atom connected to Y, or —N═, —NH—, —C(W₂)═ or —CH(W₂)— not connected to Y; X₃ and X₄ are each independently a carbon or nitrogen atom; X₅ is a carbon atom connected to Y, or —CH═ not connected to Y; wherein the 5-membered ring comprising X₁ to X₅ is aromatic or non-aromatic; W is hydrogen, halogen, C₁₋₆ alkyl, or 5- or 6-membered heterocyclyl-C₁₋₃ alkyl; W₁ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, or 5- to 8-membered heterocyclyl-C₁₋₄ alkyl; W₂ is hydrogen, halogen, C₁₋₆ alkyl, or 5- to 8-membered heterocyclyl-C₁₋₄ alkyl; L is —(CR₉R₁₀)_(m)—, —(CR₉R₁₀)_(m)—O—, —NH—, —N(C₁₋₆ alkyl)-, —S(═O)₂—, —C(CH₂)—, or C₃₋₇ cycloalkylene, wherein m is an integer of 0 to 3, and R₉ and R₁₀ are each independently hydrogen, hydroxy, halogen, or C₁₋₆ alkyl; R₁ is nitro, amino, C₁₋₆ alkylsulfonyl, haloC₁₋₆ alkoxy, or any one of the following structural formulae i) to iv):

R₂ is hydrogen, halogen, nitro, amino, C₁₋₆alkoxy, haloC₁₋₆ alkoxy, C₁₋₆ alkylsulfonyl, or 5- or 6-membered heterocycloalkyl; R₃ is hydrogen, halogen, cyano, C₁₋₆ alkyl, haloC₁₋₆ alkyl, cyanoC₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, haloC₁₋₆ alkoxy, cyanoC₁₋₆ alkoxy, C₁₋₆ alkylamino, diC₁₋₆ alkylamino, C₁₋₆ alkylthio, C₁₋₆ alkylaminocarbonyl, diC₁₋₆ alkylaminocarbonyl, C₂₋₈ alkynyl, C₆₋₁₀ aryl, haloC₆₋₁₀ aryl, 5- to 10-membered heterocyclyl, or 5- to 10-membered heterocyclylcarbonyl, wherein the heterocyclyl moiety is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C₁₋₆ alkyl, haloC₁₋₆ alkyl, C₁₋₆ alkoxy and C₁₋₆ alkoxycarbonyl; R₄ is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C₁₋₆ alkylamino, C₁₋₆ alkyl, haloC₁₋₆ alkyl, cyanoC₁₋₆ alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkoxy, cyanoC₁₋₆ alkoxy, C₃₋₈cycloalkyl-oxy, C₂₋₈ alkynyl, C₁₋₆ alkylamino-C₁₋₆ alkoxy, diC₁₋₆ alkylamino-C₁₋₆ alkoxy, C₁₋₆ alkoxy-carbonyl, carbamoyl, carbamoyl-C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, 5- to 10-membered heterocyclyl, 5- to 10-membered heterocyclyl-C₁₋₆ alkyl, 5- to 10-membered heterocyclyl-C₁₋₆ alkoxy, or 5- to 10-membered heterocyclyl-oxy, wherein the heterocyclyl moiety is optionally substituted with one or two substituents selected from the group consisting of hydroxy, oxo, C₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, diC₁₋₃ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminocarbonyl, diC₁₋₃ alkylaminocarbonyl, C₁₋₆ alkylaminosulfonyl, and non-substituted or C₁₋₆ alkyl-substituted 5- to 10-membered heterocyclyl; R₅ is hydrogen, C₁₋₆ alkyl, carbamoylC₁₋₆ alkyl, C₁₋₆ alkylaminoC₁₋₆ alkyl, diC₁₋₆ alkylaminoC₁₋₆ alkyl, or 5- to 10-membered heterocyclylC₁₋₆ alkyl, or is fused with R₆ to form C₃₋₄ alkylene; R₆ is C₁₋₆ alkyl, haloC₁₋₆ alkyl, C₁₋₆ alkoxyC₁₋₆ alkyl, C₁₋₆ alkylcarbonylC₁₋₆ alkyl, C₂₋₇ alkenyl, amino, aminoC₁₋₆ alkyl, C₃₋₇ cycloalkyl, 5- to 10-membered heterocyclyl, or 5- to 10-membered heterocyclyl-C₁₋₆ alkyl, or is fused with R₅ to form C₃₋₄ alkylene, wherein the amino moiety is optionally substituted with one or two substituents selected from hydroxy or C₁₋₆ alkyl, and the heterocyclyl moiety is optionally substituted with one to four substituents selected from the group consisting of oxo, C₁₋₆ alkyl and C₁₋₆ alkylcarbonyl; R₇ and R₈ are each independently hydrogen or C₁₋₆ alkyl; p and q are each independently 0 or 1; r is an integer of 0 to 3, and, when r is 2 or higher, R₃ moieties are the same or different; and s is an integer of 0 to 3, and, when s is 2 or higher, R₄ moieties are the same or different; all of said heterocycle or heterocyclyl moieties each independently have a saturated or unsaturated single or multiple ring and contain one to three heteroatoms selected from N, O or S; and all of said aryl moieties each independently have an aromatic single or multiple ring.
 2. The compound according to claim 1, wherein A is a saturated or unsaturated C₃₋₁₀ carbocycle, or a 5- to 10-membered heterocycle containing one to three heteroatoms selected from N, O or S; B is benzene or a 5- to 12-membered heterocycle containing one to three N atoms; C is benzene, or a 5- to 12-membered heterocycle containing one to three heteroatoms selected from N, O or S; Y is —C(═O)— connected to X₅; X₁ is —O—, —S—, —S(═O)—, —S(═O)₂—, or —N(W₁)—; X₂ is —N═, —C(W₂)═ or —CH(W₂)— not connected to Y; X₃ and X₄ are a carbon atom; X₅ is a carbon atom connected to Y; wherein the 5-membered ring comprising X₁ to X₅ is aromatic or non-aromatic; W is hydrogen, halogen, or C₁₋₆ alkyl; W₁ is hydrogen, C₁₋₆ alkyl, C₁₋₆ alkoxycarbonyl, or 5- to 8-membered heterocycloalkyl-C₁₋₄alkyl containing one or two heteroatoms selected from N or O; W₂ is hydrogen, C₁₋₆ alkyl, or 5- to 8-membered heterocycloalkyl-C₁₋₄ alkyl containing one or two heteroatoms selected from N or O; L is —(CR₉R₁₀)_(m)—, —(CR₉R₁₀)_(m)—O—, —NH—, —N(C₁₋₆ alkyl)-, —S(═O)₂—, —C(═O)—, —C(═CH₂)—, or C₃₋₇ cycloalkylene, wherein m is an integer of 0 to 3, and R₉ and R₁₀ are each independently hydrogen, hydroxy, halogen, or C₁₋₆ alkyl; R₁ is nitro, amino, C₁₋₆ alkylsulfonyl, haloC₁₋₆ alkoxy, or any one of the following structural formulae i) to iv):

R₂ is hydrogen, halogen, C₁₋₆ alkoxy, haloC₁₋₆ alkoxy, or C₁₋₆ alkylsulfonyl; R₃ is hydrogen, halogen, cyano, C₁₋₆ alkyl, haloC₁₋₆ alkyl, cyanoC₁₋₆ alkyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkoxy, haloC₁₋₆ alkoxy, cyanoC₁₋₆ alkoxy, C₁₋₆ alkylamino, diC₁₋₆ alkylamino, C₁₋₆ alkylthio, C₁₋₆ alkylaminocarbonyl, diC₁₋₆ alkylaminocarbonyl, C₂₋₈ alkynyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl containing one or two heteroatoms selected from N or S, 5- to 10-membered heterocycloalkyl containing one or two heteroatoms selected from N or O, or 5- to 10-membered heterocycloalkyl-carbonyl containing one or two heteroatoms selected from N or O; R₄ is hydrogen, halogen, hydroxy, cyano, nitro, amino, oxo, aminosulfonyl, sulfonylamido, C₁₋₆ alkylamino, C₁₋₆ alkyl, haloC₁₋₆ alkyl, cyanoC₁₋₆ alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkoxy, cyanoC₁₋₆ alkoxy, C₃₋₈ cycloalkyl-oxy, C₂₋₈ alkynyl, C₁₋₆ alkylamino-C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, carbamoyl, carbamoyl-C₁₋₆ alkoxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfonyl, 5- to 10-membered heterocyclyl-C₁₋₆ alkyl containing one or two heteroatoms selected from N or O, 5- to 10-membered heterocyclyl-C₁₋₆ alkoxy containing one or two heteroatoms selected from N or O, or 5- to 10-membered heterocyclyl-oxy containing one or two heteroatoms selected from N or O, wherein the heterocyclyl moiety is optionally substituted with one or two substituents selected from the group consisting of hydroxy, C₁₋₆ alkoxycarbonyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylcarbonyl, C₁₋₆ alkylaminocarbonyl, C₁₋₆ alkylaminosulfonyl, and non-substituted or C₁₋₆ alkyl-substituted 5- to 10-membered heterocyclyl containing one or two heteroatoms selected from N, O or S; R₅ is hydrogen, C₁₋₆ alkyl, carbamoylC₁₋₆ alkyl, C₁₋₆ alkylamino-C₁₋₆ alkyl, or 5- to 10-membered heterocycloalkyl-C₁₋₆ alkyl containing one to three heteroatoms selected from N, O or S; R₆ is C₁₋₆ alkyl, haloC₁₋₆ alkyl, C₁₋₆ alkoxyC₁₋₆ alkyl, C₁₋₆ alkylcarbonylC₁₋₆ alkyl, C₂₋₇ alkenyl, amino, aminoC₁₋₆ alkyl, C₃₋₇cycloalkyl, 5- to 10-membered heterocyclyl containing one to three heteroatoms selected from N, O or S, or 5- to 10-membered heterocyclylC₁₋₆ alkyl containing one to three heteroatoms selected from N, O or S, wherein the amino moiety is optionally substituted with one or two substituents selected from hydroxy or C₁₋₆ alkyl, and the heterocyclyl moiety is optionally substituted with one to four substituents selected from the group consisting of C₁₋₆ alkyl and C₁₋₆ alkylcarbonyl; R₇ and R₈ are each independently hydrogen or C₁₋₆ alkyl; p is 1, and q is 0 or 1; r is an integer of 0 to 3, and, when r is 2 or higher, R₃ moieties are the same or different; and s is an integer of 0 to 3, and, when s is 2 or higher, R₄ moieties are the same or different; all of said heterocycle or heterocyclyl moieties each independently have a saturated or unsaturated single or multiple ring; all of said heterocycloalkyl moieties each independently have a saturated single or multiple ring; and all of said aryl or heteroaryl moieties each independently have an aromatic single or multiple ring.
 3. The compound according to claim 2, wherein, A is a saturated or unsaturated C₆ carbocycle, or 6-membered heterocycle containing one to three N atoms, B is benzene, or a 5- to 10-membered heterocycle containing one to three N atoms, C is benzene, or a 5- to 12-membered heteroaryl containing one to three heteroatoms selected from N, O or S, L is —(CR₉R₁₀)_(m)—, —O—, —NH—, —N(C₁₋₆ alkyl)-, —S(═O)₂—, —C(═O)—, —C(═CH₂)—, or C₃₋₇ cycloalkylene, wherein m is an integer of 0 to 3, and R₉ and R₁₀ are each independently hydrogen, hydroxy, halogen or C₁₋₆ alkyl; and R₁ is nitro, amino, or any one of the following structural formulae i) to iv):

wherein R₅ to R₈ are the same as defined in claim 2; all of said heterocycle moieties each independently have a saturated or unsaturated single or multiple ring; and said heteroaryl moiety has an aromatic single or multiple ring.
 4. The compound according to claim 2, wherein A is saturated or unsaturated C₃₋₁₀ carbocycle, or 5- to 10-membered heterocycle containing one to three heteroatoms selected from N, O or S; B is benzene or a 9- to 12-membered heterocycle containing one to three N atoms; C is benzene, or a 5- to 10-membered heterocycle containing one to three heteroatoms selected from N, O or S; R₃ is hydrogen, halogen, cyano, C₁₋₆ alkyl, haloC₁₋₆ alkyl, cyanoC₁₋₆ alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkoxy, cyanoC₁₋₆ alkoxy, C₁₋₆ alkylamino, diC₁₋₆ alkylamino, C₁₋₆ alkylaminocarbonyl, diC₁₋₆ alkylaminocarbonyl, C₂₋₈ alkynyl, 5- to 10-membered heterocyclyl containing one to three heteroatoms selected from N, O or S, or 5- to 10-membered heterocycloalkyl-carbonyl containing one or two heteroatoms selected from N or O, wherein the heterocyclyl moiety is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C₁₋₆ alkyl, haloC₁₋₆ alkyl, C₁₋₆ alkoxy, and C₁₋₆ alkoxycarbonyl; and r is 0 or 1; all of said heterocycle moieties and heterocyclyl moieties each independently have a saturated or unsaturated single or multiple ring; and said heterocycloalkyl moiety has a saturated single or multiple ring.
 5. The compound according to claim 4, wherein A is a saturated or unsaturated C₆ carbocycle, or a 6-membered heterocycle containing one to three N atoms.
 6. The compound according to claim 4, wherein B is

 and R₃ is the same as defined in claim
 4. 7. The compound according to claim 1, wherein A is present or absent, and, if present, A is benzene or 6-membered heterocycle containing one to three N atoms, and if A is absent, X₃ and X₄ are each independently optionally substituted with R₁ or R₂; B is benzene, or a 6- to 10-membered heterocycle containing one to three N atoms; C is benzene, a 6- to 10-membered heterocycle containing one to three heteroatoms selected from N, O or S, or C₅₋₆ carbocycle; Y is —C(═O)— connected to X₂ or X₅; X₁ is —O—, —S—, —S(═O)—, —S(═O)₂—, or —N(W₁)—; X₂ is a carbon atom connected to Y, or —NH—, —C(W₂)═ or —CH(W₂)— not connected to Y; X₃ and X₄ are each independently a carbon or nitrogen atom; X₅ is a carbon atom connected to Y, or —CH═ not connected to Y; wherein the 5-membered ring comprising of X₁ to X₅ is aromatic or non-aromatic; W is hydrogen, C₁₋₃ alkyl, or 5- or 6-membered heterocycloalkyl-C₁₋₃ alkyl containing one or two heteroatoms selected from N or O; W₁ is hydrogen, C₁₋₃ alkyl, t-butoxycarbonyl, or 5- or 6-membered heterocycloalkyl-C₁₋₃ alkyl containing one or two heteroatoms selected from N or O; W₂ is hydrogen, halogen, or C₁₋₃ alkyl; L is —(CR₉R₁₀)_(m)—, —O—, —S(═O)₂—, C₃₋₆cycloalkylene, —NH—, —N(C₁₋₃ alkyl)-, —C(═CH₂)—, or —C(═O)—, wherein m is 0 or 1, and R₉ and R₁₀ are each independently hydrogen, halogen, hydroxy or C₁₋₃ alkyl; R₁ is any one of the following structural formulae i) to iv):

R₂ is hydrogen, halogen, nitro, amino, C₁₋₃ alkoxy, haloC₁₋₃ alkoxy, C₁₋₃ alkylsulfonyl, or 5- or 6-membered heterocycloalkyl containing one or two heteroatoms selected from N or O; R₃ is hydrogen, halogen, C₁₋₃ alkylcarbonyl, cyano, cyanoC₁₋₃ alkyl, C₁₋₃ alkyl, haloC₁₋₃ alkyl, C₂₋₃ alkynyl, haloC₁₋₃ alkoxy, cyanoC₁₋₃ alkoxy, C₁₋₆ alkoxy, C₁₋₃ alkylamino, diC₁₋₃ alkylamino, C₁₋₃ alkylaminocarbonyl, diC₁₋₃ alkylaminocarbonyl, phenyl, halophenyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heterocyclyl-carbonyl, wherein the heterocyclyl moiety contains one to three heteroatoms selected from N, O or S, and is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C₁₋₃ alkyl, haloC₁₋₃ alkyl, C₁₋₃ alkoxy, and t-butoxycarbonyl; R₄ is hydrogen, oxo, hydroxy, nitro, cyano, halogen, aminosulfonyl, amino, C₁₋₃ alkylamino, diC₁₋₃ alkylamino-C₁₋₃ alkoxy, C₁₋₃ alkylthio, C₁₋₃ alkylsulfinyl, C₁₋₃ alkylsulfonyl, C₁₋₃ alkyl, cyanoC₁₋₃ alkyl, C₂₋₄ alkynyl, C₁₋₃ alkoxy, cyanoC₁₋₃ alkoxy, haloC₁₋₃ alkoxy, carbamoyl-C₁₋₃ alkoxy, C₃₋₆ cycloalkyl-oxy, 4- to 10-membered heterocyclyl, 4- to 10-membered heterocyclyl-oxy, or 4- to 10-membered heterocyclyl-C₁₋₃ alkyl, wherein the heterocyclyl moiety contains one to three heteroatoms selected from N, O or S, and is optionally substituted with one or two substituents selected from the group consisting of hydroxy, oxo, C₁₋₃ alkyl, t-butylcarbonyl, t-butoxycarbonyl, C₁₋₃ alkylsulfonyl, diC₁₋₃ alkylsulfonyl, diC₁₋₃ alkylaminocarbonyl, 4- to 6-membered heterocyclyl and C₁₋₆ alkyl-substituted 4- to 6-membered heterocyclyl; R₅ is hydrogen, C₁₋₃ alkyl, carbamoylC₁₋₃ alkyl, diC₁₋₃ alkylamino-C₁₋₃ alkyl, or morpholino-C₁₋₃ alkyl, or is fused with R₆ to form C₃₋₄ alkylene; R₆ is C₁₋₃ alkyl, haloC₁₋₃ alkyl, C₁₋₃ alkoxyC₁₋₃ alkyl, C₂₋₃ alkenyl, amino, aminoC₁₋₃ alkyl, C₃₋₆ cycloalkyl, 5- or 6-membered heterocyclyl, or 5- or 6-membered heterocyclyl-C₁₋₃ alkyl, or is fused with R₅ to form C₃₋₄ alkylene, wherein the heterocyclyl moiety contains one to three heteroatoms selected from N, O or S, and is optionally substituted with one to four substituents selected from the group consisting of hydrogen, oxo, C₁₋₃ alkyl and acetyl, and the amino moiety is unsubstituted or substituted with one or two substituents selected from hydroxy or C₁₋₃ alkyl; R₇ is hydrogen or C₁₋₃ alkyl; R₈ is hydrogen or C₁₋₆ alkyl; p and q are each independently 0 or 1; r is 0 or 1; and s is an integer of 0 to 3, and, when s is 2 or higher, R₄ moieties are the same or different; all of said heterocycle and heterocyclyl moieties each independently have a saturated or unsaturated single or double ring.
 8. The compound according to claim 7, wherein B is

 and R₃ is the same as defined in claim
 7. 9. The compound according to claim 7, wherein m is 1; and R₉ and R₁₀ are each independently halogen, hydroxy, or C₁₋₃ alkyl.
 10. The compound according to claim 7, wherein m is 0; and R₃ is hydrogen, phenyl, halophenyl, saturated or unsaturated 5- or 6-membered heterocyclyl or 5- to 6-membered heterocyclyl-carbonyl wherein the heterocyclyl moiety contains one to three heteroatoms selected from N, O or S, and is optionally substituted with one to three substituents selected from the group consisting of halogen, hydroxy, cyano, amino, C₁₋₃ alkyl, haloC₁₋₃ alkyl, C₁₋₃ alkoxy, and t-butoxycarbonyl.
 11. The compound according to claim 7, wherein X₁ is —S— or —NH—; X₂ is —CH═ not connected to Y; X₃ and X₄ are a carbon atom; and R₁ is the structural formula i).
 12. The compound according to claim 1, which is selected from the group consisting of: 1) N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 2) 6-(methylsulfonamido)-N-(3-(2-phenylpropan-2-yl)phenyl)-1H-indole-2-carboxamide; 3) N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxamide; 4) N-(3-methoxy-5-(2-(3-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 5) N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxamide; 6) N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonyl)-1H-indole-2-carboxamide; 7) N-(3-(2-(2-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 8) 6-(methylsulfonamido)-N-(3-(2-(3-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-1H-indole-2-carboxamide; 9) N-(3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 10) N-(3-(1-(3-methoxy-5-(trifluoromethoxy)phenyl)ethyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 11) N-(3-(2-(2,4-difluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 12) N-(3-(2-(3-methoxyphenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 13) N-(3-methoxy-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 14) N-(3-bromo-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 15) N-(3-bromo-5-(2-(2,4-difluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 16) N-(3-bromo-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 17) N-(3-(difluoromethoxy)-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 18) N-(3-(2-(3-(2-amino-2-oxoethoxy)phenyl)propan-2-yl)-5-bromophenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 19) N-(3-bromo-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxamide; 20) N-(3-bromo-5-(2-(3-(difluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 21) N-(3-chloro-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 22) N-(3-bromo-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 23) N-(3-bromo-5-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 24) N-(3-chloro-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 25) N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(trifluoromethoxy)-1H-indole-2-carboxamide; 26) N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 27) N-(3-(2-(2,4-difluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 28) N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzofuran-2-carboxamide; 29) N-(3-(2-(2,4-difluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzofuran-2-carboxamide; 30) N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 31) N-(3-(2-(2-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 32) N-(3-bromo-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 33) N-(3-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 34) N-(3-methoxy-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 35) N-(3-bromo-5-(2-(2,4-difluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 36) N-(3-bromo-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 37) 5-(methylsulfonamido)-N-(3-(2-(3-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide; 38) N-(3-(2-(3-methoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 39) N-(3-(difluoromethoxy)-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 40) N-(3-chloro-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 41) N-(3-(difluoromethoxy)-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 42) N-(3-chloro-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 43) N-(3-(2-(3-(2-amino-2-oxoethoxy)phenyl)propan-2-yl)-5-bromophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 44) N-(3-(2-(5-(2-amino-2-oxoethoxy)-2-fluorophenyl)propan-2-yl)-5-bromophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 45) N-(3-(2-(3-((1-amino-2-methyl-1-oxopropan-2-yl)oxy)phenyl)propan-2-yl)-5-bromophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 46) N-(3-bromo-5-(2-(3-(difluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 47) N-(3-bromo-5-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 48) N-(3-bromo-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 49) N-(3-bromo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 50) N-(3-bromo-5-(2-(3-(morpholinomethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 51) N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 52) N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-3-methyl-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 53) N-(3-bromo-5-(3-(4-fluorophenyl)pentan-3-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 54) N-(3-methoxy-5-(3-(3-methoxy-5-(trifluoromethoxy)phenyl)pentan-3-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 55) N-(3-methoxy-5-(3-(3-methoxy-5-(trifluoromethoxy)phenyl)pentan-3-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 56) N-(3-bromo-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-b]pyridine-2-carboxamide; 57) N-(3-chloro-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-b]pyridine-2-carboxamide; 58) N-(3-chloro-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 59) N-(3-chloro-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 60) N-(3-bromo-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[3,2-b]pyridine-2-carboxamide; 61) N-(3-bromo-5-(2-(3-ethoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-c]pyridine-2-carboxamide; 62) N-(3-chloro-5-(2-(2-fluoro-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 63) N-(3-fluoro-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 64) N-(3-chloro-5-(2-phenylpropan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 65) N-(3-chloro-5-(2-(3-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 66) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)-4-morpholinobenzo[b]thiophene-2-carboxamide; 67) N-(3-chloro-5-(2-(3-fluoro-5-methoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 68) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 69) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-b]pyridine-2-carboxamide; 70) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[3,2-b]pyridine-2-carboxamide; 71) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-c]pyridine-2-carboxamide; 72) N-(3-chloro-5-(2-(3-isobutoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 73) N-(3-chloro-5-(2-(3-propoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 74) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)imidazo[1,2-a]pyridine-2-carboxamide; 75) N-(3-(2-(3-(but-2-yn-1-yloxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 76) N-(3-chloro-5-(2-(3-(oxetan-3-yloxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 77) N-(3-chloro-5-(2-(3-(cyanomethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 78) N-(3-(2-(3-(allyloxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 79) N-(3-chloro-5-(2-(3-cyclopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 80) N-(3-chloro-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 81) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[d]thiazole-2-carboxamide; 82) N-(3-fluoro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 83) N-(3-chloro-5-(2-(3-(2,2-difluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 84) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 85) N-(3-fluoro-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 86) N-(3-fluoro-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-c]pyridine-2-carboxamide; 87) N-(3-bromo-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 88) N-(3-chloro-5-(2-(3-(2,2,2-trifluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 89) N-(3-bromo-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)thieno[2,3-c]pyridine-2-carboxamide; 90) N-(3-chloro-5-(2-(3-(2-morpholinoethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 91) N-(3-(2-(3-bromo-5-isopropoxyphenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 92) N-(3-chloro-5-(2-(3-chloro-5-isopropoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 93) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-4-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 94) N-(3-chloro-5-(2-(3-(2-(dimethylamino)ethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 95) tert-butyl 4-(3-(2-(3-chloro-5-(5-(methylsulfonamido)benzo[b]thiophene-2-carboxamido)phenyl)propan-2-yl)-5-(trifluoromethoxy)phenoxy)piperidine-1-carboxylate; 96) N-(3-chloro-5-(2-(3-(piperidin-4-yloxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 97) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide; 98) N-(3-bromo-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide; 99) N-(3-bromo-5-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide 2,2,2-trifluoroacetate; 100) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 101) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide; 102) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-4-(methylsulfonamido)thiophene-2-carboxamide; 103) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(morpholine-4-sulfonamido)benzo[b]thiophene-2-carboxamide; 104) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide; 105) 6-chloro-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 106) N-(3-chloro-5-(2-(3-methoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 107) N-(3-ethynyl-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 108) N-(3-ethynyl-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 109) N-(3-(2-(2,4-difluorophenyl)propan-2-yl)-5-ethynylphenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 110) 3-chloro-N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 111) 3-chloro-N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 112) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-7-methoxy-5-(methylsulfonamido)benzofuran-2-carboxamide; 113) N-(3-(2-(4-fluorophenyl)propan-2-yl)phenyl)-7-methoxy-5-(methylsulfonamido)benzofuran-2-carboxamide; 114) N-(3-chloro-5-(2-(3-(prop-1-yn-1-yl)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 115) N-(3-bromo-5-(2-(3-((4-methylpiperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 116) tert-butyl 4-(3-(2-(3-bromo-5-(5-(methylsulfonamido)benzo[b]thiophene-2-carboxamido)phenyl)propan-2-yl)benzyl)piperazine-1-carboxylate; 117) tert-butyl 4-(3-(2-(3-bromo-5-(6-(methylsulfonamido)-1H-indole-2-carboxamido)phenyl)propan-2-yl)benzyl)piperazine-1-carboxylate; 118) N-(3-bromo-5-(2-(3-(piperazin-1-ylmethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 119) N-(3-bromo-5-(2-(3-(piperazin-1-ylmethyl)phenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 120) N-(3-(2-(3-((1H-imidazol-1-yl)methyl)phenyl)propan-2-yl)-5-bromophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 121) N-(3-chloro-5-(2-(3-((2-hydroxyazetidin-1-yl)methyl)-5-isopropoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 122) N-(3-bromo-5-(2-(3-isopropoxy-5-(morpholinomethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 123) tert-butyl 4-(3-(2-(3-bromo-5-(5-(methylsulfonamido)benzo[b]thiophene-2-carboxamido)phenyl)propan-2-yl)-5-isopropoxybenzyl)piperazine-1-carboxylate; 124) N-(3-bromo-5-(2-(3-isopropoxy-5-(piperazin-1-ylmethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 125) N-(3-chloro-5-(2-(3-isopropoxy-5-(pyrrolidin-1-ylmethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 126) N-(3-chloro-5-(2-(3-isopropoxy-5-(morpholinomethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 127) N-(3-chloro-5-(2-(3-isopropoxy-5-((4-pivaloylpiperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 128) N-(3-chloro-5-(2-(3-isopropoxy-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 129) N-(3-chloro-5-(2-(3-isopropoxy-5-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)piperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 130) N-(3-chloro-5-(2-(3-isopropoxy-5-((4-(oxetan-3-yl)piperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 131) N-(3-chloro-5-(2-(3-((4-(N,N-dimethylsulfamoyl)piperazin-1-yl)methyl)-5-isopropoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 132) N-(3-chloro-5-(2-(3-((1,1-dioxidothiomorpholino)methyl)-5-isopropoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 133) 4-(3-(2-(3-chloro-5-(5-(methylsulfonamido)benzo[b]thiophene-2-carboxamido)phenyl)propan-2-yl)-5-isopropoxybenzyl)-N,N-dimethylpiperazine-1-carboxamide; 134) N-(3-(2-(3-((2-oxa-7-azaspiro[3,5]nonan-7-yl)methyl)-5-isopropoxyphenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 135) N-(3-chloro-5-(2-(3-isopropoxy-5-((4-(5-isopropyl-1,3,4-oxadiazol-2-yl)piperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 136) N-(3-fluoro-5-(2-(3-isopropoxy-5-((4-(5-isopropyl-1,2,4-oxadiazol-3-yl)piperazin-1-yl)methyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 137) N-(3-fluoro-5-(2-(3-isopropoxy-5-(morpholinomethyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 138) N-(3-chloro-5-(2-(3-((1-methyl-1H-pyrazol-4-yl)methyl)-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 139) N-(3-bromo-5-(2-(3-((4-(N,N-dimethylsulfamoyl)piperazin-1-yl)methyl)-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 140) N-(3-fluoro-5-(2-(3-(morpholinomethyl)-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 141) N-(3-bromo-5-(2-(3-((4-(oxetan-3-yl)piperazin-1-yl)methyl)-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 142) N-(3-chloro-5-(2-(3-isopropoxy-5-(1-methyl-1H-pyrazol-5-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 143) N-(3-chloro-5-(2-(3-isopropoxy-5-(1-methyl-1H-pyrazol-4-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 144) N-(3-chloro-5-(2-(3-(3-hydroxy-4-methylpiperazin-1-yl)-5-isopropoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 145) N-(3-chloro-5-(2-(3-isopropoxy-5-morpholinophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 146) N-(3-chloro-5-(2-(3-isopropoxy-5-(pyrrolidin-1-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 147) N-(3-chloro-5-(2-(3-isopropoxy-5-(4-methylpiperazin-1-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 148) N-(6-chloro-4-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 149) N-(2-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 150) N-(4-chloro-6-(2-(3-methoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 151) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-2-(methylsulfonamido)thieno[2,3-b]pyrazine-6-carboxamide; 152) N-(3-(2-(4-bromophenyl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 153) N-(3-chloro-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 154) N-(3-chloro-5-(2-(2,4-dimethoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 155) N-(3-chloro-5-(2-(4-methoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 156) N-(3-chloro-5-(2-(2,5-dimethoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 157) N-(3-chloro-5-(2-(4-(methylthio)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 158) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 159) N-(3-chloro-5-(2-(4-(1-methyl-1H-pyrazol-5-yl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 160) N-(3-chloro-5-(2-(4-(methylsulfinyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 161) N-(3-chloro-5-(2-(4-(methylsulfonyl)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 162) N-(3-chloro-5-(2-(3,4-difluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 163) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; 164) N-(3-chloro-5-(2-(piperidin-1-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 165) 6-chloro-N-(3-chloro-5-(2-(piperidin-1-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 166) N-(3-(2-(1H-pyrrol-2-yl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 167) N-(3-(2-(1H-pyrrol-3-yl)propan-2-yl)-5-chlorophenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 168) N-(3-chloro-5-(2-(1-methyl-1H-pyrrol-3-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 169) N-(3-chloro-5-(2-(1-methyl-1H-pyrrol-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 170) N-(3-chloro-5-(2-(thiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 171) N-(3-chloro-5-(2-(thiophen-3-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 172) 6-chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 173) 6-bromo-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 174) N-(3-chloro-5-(2-(5-chlorothiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 175) 6-chloro-N-(3-chloro-5-(2-(5-chlorothiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 176) N-(3-chloro-5-(2-(2-methoxythiophen-3-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 177) N-(3-chloro-5-(2-(5-methoxythiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 178) N-(3-chloro-5-(2-(5-methylthiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 179) 6-chloro-N-(3-chloro-5-(2-(5-methylthiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 180) 6-chloro-N-(3-chloro-5-(2-(5-isopropylthiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 181) 6-chloro-N-(3-chloro-5-(2-(4-methylthiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 182) 6-chloro-N-(3-chloro-5-(2-(4-fluorophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 183) 6-chloro-N-(3-chloro-5-(2-(4-methoxyphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 184) 5-chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 185) 6-chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(2-methoxyethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; 186) 6-chloro-N-(3-chloro-5-(2-(5-cyanothiophen-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 187) N-(3-chloro-5-(2-(1-ethyl-1H-pyrrol-2-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 188) 6-chloro-N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-((2-hydroxyethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; 189) N-(3-chloro-5-(2-(pyrimidin-2-yloxy)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 190) N-(3-chloro-5-(2-(6-oxopyridazin-1(6H)-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 191) N-(3-chloro-5-(2-(pyridin-4-yl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 192) 2-((3-bromo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl dihydrogen phosphate; 193) 2-((3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl dihydrogen phosphate; 194) tert-butyl (2-((3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)carbamoyl)benzo[b]thiophen-5-yl)carbamate; 195) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((2-methoxyethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; 196) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(((tetrahydrofuran-3-yl)methyl)sulfonamido)benzo[b]thiophene-2-carboxamide; 197) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(((tetrahydrofuran-2-yl)methyl)sulfonamido)benzo[b]thiophene-2-carboxamide; 198) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(((tetrahydro-2H-pyran-4-yl)methyl)sulfonamido)benzo[b]thiophene-2-carboxamide; 199) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((3,5-dimethylisoxazole)-4-sulfonamido)benzo[b]thiophene-2-carboxamide; 200) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((1-methyl-1H-pyrazole)-3-sulfonamido)benzo[b]thiophene-2-carboxamide; 201) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((1-methyl-1H-pyrazole)-4-sulfonamido)benzo[b]thiophene-2-carboxamide; 202) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(ethylsulfonamido)benzo[b]thiophene-2-carboxamide; 203) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((1-methylethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; 204) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxamide; 205) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((1,1-dioxidotetrahydro-2H-thiopyran)-4-sulfonamido)benzo[b]thiophene-2-carboxamide; 206) 5-((1-acetylpiperidine)-4-sulfonamido)-N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)benzo[b]thiophene-2-carboxamide; 207) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(vinylsulfonamido)benzo[b]thiophene-2-carboxamide; 208) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((2-(dimethylamino)ethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; 209) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(2-morpholinoethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; 210) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-((2-(hydroxy(methyl)amino)ethyl)sulfonamido)benzo[b]thiophene-2-carboxamide; 211) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(1,1-dioxido-1,2-thiazinan-2-yl)benzo[b]thiophene-2-carboxamide; 212) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(1,1-dioxidoisothiazolidin-2-yl)benzo[b]thiophene-2-carboxamide; 213) N-(3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 214) 3-iodo-N-(3-iodo-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 215) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; 216) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-N-methyl-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; 217) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-5-(N-(2-morpholinoethyl)methylsulfonamido)benzo[b]thiophene-2-carboxamide; 218) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-fluoro-N-(2-morpholinoethyl)-5-(N-(2-morpholinoethyl)methylsulfonamido)benzo[b]thiophene-2-carboxamide; 219) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(N-(2-(dimethylamino)ethyl)methylsulfonamido)-6-fluorobenzo[b]thiophene-2-carboxamide; 220) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; 221) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; 222) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide 1,1-dioxide; 223) N-(3-chloro-5-(2-(3-isopropoxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide 1-oxide; 224) N-(3-(2-(3-cyanophenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 225) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide; 226) 6-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 227) 5-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 228) 3-methyl-5-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 229) N-(4′-fluoro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-nitroindoline-2-carboxamide; 230) 6-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)indoline-2-carboxamide; 231) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-nitroindoline-2-carboxamide; 232) 6-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)benzo[d]thiazole-2-carboxamide; 233) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-nitro-1H-benzo[d]imidazole-2-carboxamide; 234) 5-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazole-2-carboxamide; 235) N-(4′-fluoro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-5-nitro-1H-benzo[d]imidazole-2-carboxamide; 236) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxamide; 237) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 238) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzofuran-2-carboxamide; 239) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxamide; 240) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonyl)-1H-indole-2-carboxamide; 241) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 242) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 243) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3-methyl-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 244) N-(4′-fluoro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide; 245) N-(5-acetyl-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 246) N-(4-(2,4-difluorophenyl)-1H-indazol-6-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 247) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-nitro-1H-indole-2-carboxamide; 248) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-(methylsulfonamido)-1H-indole-2-carboxamide; 249) 1-methyl-6-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 250) 1-methyl-5-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 251) 3-methyl-1-(2-morpholinoethyl)-5-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 252) 1-(2-morpholinoethyl)-6-nitro-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 253) 1-methyl-6-(methylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 254) 2-((2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indol-6-yl)oxy)-2-methylpropanoic acid; 255) ethyl 2-((2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indol-6-yl)oxy)acetate; 256) 2-((2-((2′,4′-difluoro-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indol-6-yl)oxy)acetic acid; 257) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxamide; 258) 5-amino-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 259) 5-(methylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 260) 6-(methylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 261) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)indoline-2-carboxamide; 262) N-(4′-fluoro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)indoline-2-carboxamide; 263) tert-butyl 6-nitro-2-((2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)carbamoyl)-1H-indole-1-carboxylate; 264) 6-(2,2,2-trifluoroethylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 265) 6-(sulfamoylamino)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 266) 6-(methylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-3-carboxamide; 267) 6-((N,N-dimethylsulfamoyl)amino)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 268) N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(trifluoromethylsulfonamido)-1H-indole-2-carboxamide; 269) 6-((N-methylsulfamoyl)amino)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 270) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 271) 6-amino-N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 272) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)-1H-indole-2-carboxamide; 273) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(2,2,2-trifluoroethylsulfonamido)-1H-indole-2-carboxamide; 274) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(sulfamoylamino)-1H-indole-2-carboxamide; 275) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-3-carboxamide; 276) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-((N,N-dimethylsulfamoyl)amino)-1H-indole-2-carboxamide; 277) N-(4′-fluoro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 278) 6-(cyclopropanesulfonamido)-N-(4-(2,4-difluorophenyl)pyridin-2-yl)-1H-indole-2-carboxamide; 279) N-(4-(2,4-difluorophenyl)pyridin-2-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 280) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-N-methyl-6-(methylsulfonamido)-1H-indole-2-carboxamide; 281) N-(5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 282) N-(5′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide; 283) 6-(methylsulfonamido)-N-(4′-sulfamoyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 284) N-(4′-cyano-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 285) 6-(methylsulfonamido)-N-(4′-nitro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 286) methyl 3′-(6-nitro-1H-indole-2-carboxamido)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylate; 287) methyl 3′-(6-(methylsulfonamido)-1H-indole-2-carboxamido)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylate; 288) methyl 4-methoxy-3′-(6-nitro-1H-indole-2-carboxamido)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylate; 289) methyl 4-methoxy-3′-(6-(methylsulfonamido)-1H-indole-2-carboxamido)-6-(trifluoromethyl)-[1,1′-biphenyl]-3-carboxylate; 290) 6-(methylsulfonamido)-N-(3-(3-(trifluoromethyl)pyridin-2-yl)phenyl)-1H-indole-2-carboxamide; 291) 6-(methylsulfonamido)-N-(3-(4-(trifluoromethyl)pyridin-3-yl)phenyl)-1H-indole-2-carboxamide; 292) 6-nitro-N-(3-(2-(trifluoromethyl)pyridin-3-yl)phenyl)-1H-indole-2-carboxamide; 293) 6-(methylsulfonamido)-N-(3-(2-(trifluoromethyl)pyridin-3-yl)phenyl)-1H-indole-2-carboxamide; 294) N-(3-(6-chloro-4-(trifluoromethyl)pyridin-3-yl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 295) N-(2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)-6-nitro-1H-indole-2-carboxamide; 296) tert-butyl 2-((2′-fluoro-4′-methoxy-[1,1′-biphenyl]-3-yl)carbamoyl)-6-(methylsulfonamido)-1H-indole-1-carboxylate; 297) N-(4-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)-6-nitro-1H-indole-2-carboxamide; 298) methyl 6-chloro-3′-(6-nitro-1H-indole-2-carboxamido)-[1,1′-biphenyl]-3-carboxylate; 299) methyl 6-chloro-3′-(6-(methylsulfonamido)-1H-indole-2-carboxamido)-[1,1′-biphenyl]-3-carboxylate; 300) methyl 4-chloro-3-(2-(6-(methylsulfonamido)-1H-indole-2-carboxamido)pyridin-4-yl)benzoate; 301) N-(5-cyano-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 302) N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 303) N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-methoxy-6-(methylsulfonamido)-1H-indole-2-carboxamide; 304) N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonyl)-1H-indole-2-carboxamide; 305) N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 306) N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzofuran-2-carboxamide; 307) N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-((N-methylsulfamoyl)amino)-1H-indole-2-carboxamide; 308) N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(trifluoromethoxy)-1H-indole-2-carboxamide; 309) N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 310) N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 311) N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3-methyl-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 312) 6-(methylsulfonamido)-N-(2′,4′,5-trifluoro-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 313) N-(2′,4′-difluoro-5-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 314) N-(2′,4′-difluoro-5-methoxy-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 315) N-(5-cyano-4′-fluoro-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 316) N-(2′,4′-difluoro-5-methoxy-[1,1′-biphenyl]-3-yl)-3-methyl-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 317) N-(2′,4′-difluoro-5-methoxy-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 318) N-(2′,4′-difluoro-5-(methylcarbamoyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 319) N-(5-(dimethylcarbamoyl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 320) N-(2′,4′-difluoro-5-(piperidine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 321) N-(2′,4′-difluoro-5-(morpholine-4-carbonyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 322) N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 323) N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 324) N-(5-chloro-3′-methoxy-5′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 325) N-(5-chloro-3′-methoxy-5′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)-6-fluoro-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 326) N-(5-chloro-3′-methoxy-5′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)-6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; 327) N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxamide; 328) N-(5-chloro-3′-methoxy-5′-(trifluoromethoxy)-[1,1′-biphenyl]-3-yl)-5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxamide; 329) N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; 330) N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-fluoro-5-((tetrahydrofuran)-3-sulfonamido)benzo[b]thiophene-2-carboxamide; 331) N-(4-chloro-6-(2,4-difluorophenyl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 332) N-(3-chloro-5-(thiophen-3-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 333) 6-chloro-N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 334) N-(3-chloro-5-(1-methyl-1H-pyrrol-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 335) N-(5-chloro-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-3-hydroxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 336) N-(3-chloro-5-(thiophen-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 337) N-(6-chloro-4-(2,4-difluorophenyl)pyridin-2-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 338) N-(3-chloro-5-(pyrazin-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 339) N-(3-chloro-5-(6-chloropyrazin-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 340) N-(3-chloro-5-(1-methyl-1H-imidazol-5-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 341) N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide; 342) N-(5-bromo-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide; 343) 1-methyl-6-(N-methylmethylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 344) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide; 345) N-(2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1-methyl-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide; 346) 6-(N-methylmethylsulfonamido)-N-(2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-1H-indole-2-carboxamide; 347) N-(2′,4′-difluoro-5-methoxy-[1,1′-biphenyl]-3-yl)-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide; 348) N-(2′,4′-difluoro-5-methoxy-[1,1′-biphenyl]-3-yl)-1-methyl-6-(N-methylmethylsulfonamido)-1H-indole-2-carboxamide; 349) N-(2′,4′-difluoro-5-(6-fluoropyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 350) tert-butyl 2-(2′,4′-difluoro-5-(6-(methylsulfonamido)-1H-indole-2-carboxamido)-[1,1′-biphenyl]-3-yl)-1H-pyrrole-1-carboxylate; 351) N-(2′,4′-difluoro-5-(1H-pyrazol-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 352) N-(2′,4′-difluoro-5-(1H-pyrrol-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 353) N-(2′,4′-difluoro-5-(1-methyl-1H-pyrrol-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 354) N-(2′,4′-difluoro-5-(thiophen-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 355) N-(2′,4′-difluoro-5-(thiophen-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 356) N-(2′,4′-difluoro-5-(pyridin-4-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 357) N-(2′,4′-difluoro-5-(pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 358) N-(2′,4′-difluoro-5-(6-(trifluoromethyl)pyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 359) N-(5-(6-cyanopyridin-3-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 360) N-(2′,4′-difluoro-5-(pyrimidin-5-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 361) N-(5-(2-aminopyrimidin-5-yl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 362) 6-(methylsulfonamido)-N-(2,2″,4,4″-tetrafluoro-[1,1′:3′,1″-terphenyl]-5′-yl)-1H-indole-2-carboxamide; 363) N-(5-(cyanomethyl)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 364) N-(2′,4′-difluoro-5-(6-hydroxypyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 365) N-(5-ethynyl-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 366) N-(5-(2,2-difluoroethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 367) N-(2′,4′-difluoro-5-isobutoxy-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 368) N-(5-(cyanomethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 369) N-(5-(difluoromethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 370) N-(5-(difluoromethoxy)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 371) N-(2′,4′-difluoro-5-(piperidin-1-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 372) N-(5-(dimethylamino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 373) N-(2′,4′-difluoro-5-(methylamino)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 374) N-(2′,4′-difluoro-5-morpholino-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 375) N-(5-(dimethylamino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 376) N-(5-(dimethylamino)-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-5-(methylsulfonamido)benzofuran-2-carboxamide; 377) N-(5′-carbamoyl-4′-methoxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 378) N-(5′-carbamoyl-4′-hydroxy-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 379) N-(5′-carbamoyl-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 380) N-(5′-carbamoyl-2′-chloro-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 381) N-(4-(5-carbamoyl-2-chlorophenyl)pyridin-2-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 382) N-(2′,4′-difluoro-5-(6-methoxypyridin-3-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 383) N-(2′,4′-difluoro-5-(6-methoxypyridin-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 384) N-(2′,4′-difluoro-5-(6-hydroxypyridin-2-yl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 385) N-(4′-amino-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 386) N-(4′-(methylamino)-2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 387) N-(3-(difluoro(phenyl)methyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 388) N-(3-(difluoro(pyridin-4-yl)methyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 389) N-(3-(difluoro(pyridin-2-yl)methyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 390) N-(3-((3-cyanophenyl)difluoromethyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 391) N-(3-((3-cyanophenyl)difluoromethyl)-5-(2,2-difluoroethoxy)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 392) N-(3-((3-cyanophenyl)difluoromethyl)-5-isobutoxyphenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 393) N-(3-(cyanomethoxy)-5-((3-cyanophenyl)difluoromethyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 394) N-(3-((4-methoxyphenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 395) 6-(methylsulfonamido)-N-(3-(phenylsulfonyl)phenyl)-1H-indole-2-carboxamide; 396) 6-(methylsulfonamido)-N-(3-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-1H-indole-2-carboxamide; 397) N-(3-methoxy-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 398) 6-(methylsulfonamido)-N-(3-((3-(trifluoromethoxy)phenyl)sulfonyl)-5-(trifluoromethyl)phenyl)-1H-indole-2-carboxamide; 399) N-(3-cyano-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 400) N-(3-isobutoxy-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 401) N-(3-(2,2-difluoroethoxy)-5-((3-(trifluoromethoxy)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 402) N-(3-((3-cyanophenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 403) 6-(methylsulfonamido)-N-(3-(pyridin-2-ylsulfonyl)phenyl)-1H-indole-2-carboxamide; 404) 6-(methylsulfonamido)-N-(3-(pyridin-3-ylsulfonyl)phenyl)-1H-indole-2-carboxamide; 405) N-(3-((3-chlorophenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 406) N-(3-((6-cyanopyridin-2-yl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 407) N-(3-((5-methoxypyridin-3-yl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 408) N-(3-((6-methoxypyridin-2-yl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 409) N-(3-(benzo[b]thiophen-5-ylsulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 410) N-(3-((2-methylbenzo[d]thiazol-6-yl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 411) N-(3-((3-cyano-5-methoxyphenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 412) N-(3-((3-(cyanomethyl)phenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 413) 6-(methylsulfonamido)-N-(3-((4-oxo-4H-chromen-7-yl)sulfonyl)phenyl)-1H-indole-2-carboxamide; 414) N-(3-((3-bromophenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 415) N-(3-((3-aminophenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 416) N-(3-((3-ethynylphenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 417) N-(3-((3-cyano-5-hydroxyphenyl)sulfonyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 418) N-(3-bromo-5-((7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 419) N-(3-bromo-5-((5,7-difluoro-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 420) N-(3-bromo-5-((4,4-difluoropiperidin-1-yl)sulfonyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 421) 5-(methylsulfonamido)-N-(3-(1-phenylcyclopropyl)phenyl)benzo[b]thiophene-2-carboxamide; 422) 6-(methylsulfonamido)-N-(3-(1-phenylcyclopropyl)phenyl)-1H-indole-2-carboxamide; 423) 5-(methylsulfonamido)-N-(3-(1-phenylvinyl)phenyl)benzo[b]thiophene-2-carboxamide; 424) N-(3-(1-(4-fluorophenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 425) N-(3-(1-(4-fluorophenyl)cyclopropyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 426) N-(3-bromo-5-(1-(2,4-difluorophenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 427) N-(3-methoxy-5-(1-(3-methoxy-5-(trifluoromethoxy)phenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 428) N-(3-(difluoromethoxy)-5-(1-(4-fluorophenyl)cyclopropyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 429) N-(3-(difluoromethoxy)-5-(1-(4-fluorophenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 430) N-(3-chloro-5-(1-(3-isopropoxy-5-(trifluoromethoxy)phenyl)cyclopropyl)phenyl)-6-fluoro-5-(N-methylmethylsulfonamido)benzo[b]thiophene-2-carboxamide; 431) N-(3-chloro-5-(1-(3-isopropoxy-5-(trifluoromethoxy)phenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 432) N-(3-chloro-5-(1-(4-chlorophenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 433) 6-chloro-N-(3-chloro-5-(1-(4-chlorophenyl)cyclopropyl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 434) N-(3-benzoylphenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 435) N-(3-(1-hydroxy-1-phenylethyl)phenyl)-6-(methylsulfonamido)-1H-indole-2-carboxamide; 436) 6-(N-(2-amino-2-oxoethyl)methylsulfonamido)-N-(3-(2-(3-hydroxy-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-1H-indole-2-carboxamide; 437) N-(3-(2-(3-(2-amino-2-oxoethoxy)-5-(trifluoromethoxy)phenyl)propan-2-yl)phenyl)-6-(N-(2-amino-2-oxoethyl)methylsulfonamido)-1H-indole-2-carboxamide; 438) N-(3-chloro-5-((2,4-difluorophenyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 439) N-(3-chloro-5-((2,4-difluorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 440) N-(3-chloro-5-((4-chlorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 441) 6-chloro-N-(3-chloro-5-((4-chlorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 442) 6-chloro-N-(3-chloro-5-((2,4-difluorophenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 443) N-(3-chloro-5-((3-isopropoxy-5-(trifluoromethoxy)phenyl)(methyl)amino)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 444) N-(3-chloro-5-(2,4-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 445) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 446) N-(3-chloro-5-(4-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 447) N-(3-chloro-5-(4-methoxyphenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 448) N-(3-chloro-5-(2,5-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 449) 6-chloro-N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 450) N-(3-chloro-5-(3-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 451) N-(3-chloro-5-(4-cyanophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 452) N-(3-chloro-5-(3-isopropoxy-5-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 453) 6-bromo-N-(3-chloro-5-(4-chlorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 454) N-(3-chloro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 455) N-(3-chloro-5-(3-(trifluoromethyl)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 456) N-(3-chloro-5-(3-chlorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 457) N-(3-chloro-5-(3-methoxyphenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 458) N-(3-chloro-5-(3-chloro-5-cyanophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 459) N-(3-chloro-5-(3-cyanophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 460) N-(3-chloro-5-(3,4-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 461) N-(3-chloro-5-(3-chloro-4-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 462) N-(3-chloro-5-(2,4-dichlorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 463) N-(3-chloro-5-(3,5-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 464) N-(3-chloro-5-(3,5-dichlorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 465) N-(3-chloro-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 466) N-(3-chloro-5-(4-chloro-3-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 467) N-(3-chloro-5-(3-chloro-5-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 468) N-(3-chloro-5-(4-chloro-3-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 469) N-(3-chloro-5-(3-chloro-5-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 470) N-(3-chloro-5-(4-fluoro-3-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 471) 6-chloro-N-(3-chloro-5-(thiazol-2-yloxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 472) 6-chloro-N-(3-chloro-5-(thiazol-5-yloxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 473) 6-chloro-N-(3-chloro-5-((5-chlorothiophen-2-yl)oxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 474) 6-chloro-N-(3-chloro-5-(3-chloro-5-methoxyphenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 475) 6-chloro-N-(3-chloro-5-(3-chloro-5-hydroxyphenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 476) 6-chloro-N-(3-chloro-5-(3-chloro-4-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 477) 6-chloro-N-(3-chloro-5-(4-chloro-3-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 478) 6-chloro-N-(3-chloro-5-(4-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 479) 6-chloro-N-(3-chloro-5-(3-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 480) 6-chloro-N-(3-chloro-5-(4-(trifluoromethoxy)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 481) 6-chloro-N-(3-chloro-5-(3,4-difluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 482) 6-chloro-N-(3-chloro-5-(4-(trifluoromethyl)phenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 483) 6-chloro-N-(3-chloro-5-(3-chloro-5-fluorophenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 484) 6-chloro-N-(3-chloro-5-(3-fluoro-5-methoxyphenoxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 485) 5-chloro-N-(3-chloro-5-(4-chlorophenoxy)phenyl)-6-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 486) 6-chloro-N-(3-chloro-5-(cyclohexyloxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 487) 6-chloro-N-(3-chloro-5-((5-methylthiophen-2-yl)oxy)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 488) 4-bromo-N-(3-chloro-5-(2-(3-isopropoxy-5-methylphenyl)propan-2-yl)phenyl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 489) ro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 490) 6-chloro-N-(2-chloro-6-(4-chlorophenoxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 491) N-(2-chloro-6-((6-chloropyridin-3-yl)oxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 492) 6-chloro-N-(2-chloro-6-((6-chloropyridin-3-yl)oxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 493) N-(2-chloro-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 494) 6-chloro-N-(2-chloro-6-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 495) N-(2-chloro-6-(4-(trifluoromethyl)phenoxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 496) 6-chloro-N-(2-chloro-6-(4-(trifluoromethyl)phenoxy)pyridin-4-yl)-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; 497) N-(3-chloro-5-(2-(4-chlorophenyl)propan-2-yl)phenyl)-6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide; and 498) N-(3-chloro-5-(4-chlorophenoxy)phenyl)-6-methoxy-5-(methylsulfonamido)benzo[b]thiophene-2-carboxamide.
 13. A pharmaceutical composition for preventing or treating diseases associated with the activation of STAT3 protein, comprising the compound as defined in claim 1 as an active ingredient.
 14. The pharmaceutical composition according to claim 13, wherein the diseases associated with the activation of STAT3 protein is selected from the group consisting of solid cancers, hematological or blood cancers, radio- or chemo-resistant cancers, metastatic cancers, inflammatory diseases, immunological diseases, diabetes, macular degeneration, human papillomavirus infection and tuberculosis.
 15. The pharmaceutical composition according to claim 13, wherein the diseases associated with the activation of STAT3 protein are selected from the group consisting of breast cancer, lung cancer, stomach cancer, prostate cancer, uterine cancer, ovarian cancer, kidney cancer, pancreatic cancer, liver cancer, colon cancer, skin cancer, head and neck cancer, thyroid cancer, osteosarcoma, acute or chronic leukemia, multiple myeloma, B- or T-cell lymphoma, non-Hodgkin's lymphoma, auto-immune diseases comprising rheumatoid arthritis, psoriasis, hepatitis, inflammatory bowel disease, Crohn's disease, diabetes, macular degeneration, human papillomavirus infection, and tuberculosis.
 16. A use of the compound as defined in claim 1 for the manufacture of a medicament for preventing or treating diseases associated with the activation of STAT3 protein.
 17. A method for preventing or treating diseases associated with the activation of STAT3 protein in a mammal, which comprises administering the compound as defined in claim 1 to the mammal.
 18. A method for the manufacture of a medicament for preventing or treating diseases associated with the activation of STAT3 protein comprising a step of preparing a medicament comprising the compound as defined in claim
 1. 